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The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822

HIV-chemotherapy and -prophylaxis: new drugs,
leads and approaches
Erik De Clercq∗
Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

In recent years, significant progress has been made towards the chemotherapy (and prophylaxis) of HIV infections. This
progress is situated at three different levels. (i) New anti-HIV drugs have been approved for clinical use and have entered the
market: the virus entry inhibitor enfuvirtide (FuzeonTM ), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine
(EmtrivaTM ), the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate (VireadTM ) and the HIV
protease inhibitor (PI) atazanavir (ReyatazTM ). (ii) Other compounds have proceeded through preclinical and/or clinical
development: CXCR4 antagonists (i.e. AMD070), CCR5 antagonists (i.e. SCH-C), NRTIs (such as amdoxovir), NNRTIs
(such as etravirine), integrase inhibitors (such as S-1360) and PIs (such as tipranavir). (iii) Yet other compounds, acting by
novel mechanisms, have recently been identified as anti-HIV agents that seem worthy of further (pre)clinical development:
cell receptor CD4 down-modulators (i.e. cyclotriazadisulfonamides), viral envelope gp120-binding agents such as plant
lectins and glycopeptide antibiotics, HIV integrase inhibitors such as the pyranodipyrimidine V-165, and two new classes
of compounds (i.e. N-aminoimidazoles and pyridine oxide derivatives) which seem to interfere with a post-integration,
transcription transactivation event. Taken together, it is obvious that the approaches for the treatment of HIV infections in
recent years have become both more diverse and more efficient.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: HIV; Chemotherapy; Chemoprophylaxis; Anti-HIV drugs


1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1801
2. Cellular CD4 receptor down-modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1801
3. Viral glycoprotein gp120 binders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1802
4. CXCR4 and CCR5 antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1803
5. Virus–cell fusion inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805
6. Nucleoside reverse transcriptase inhibitors (NRTIs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1806
7. Nucleotide reverse transcriptase inhibitors (NtRTIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1807
8. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1809
9. HIV integrase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1810
10. Transcription (transactivation) inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1812

∗ Tel.: +32-16-337341; fax: +32-16-337340.
E-mail address: (E. De Clercq).

1357-2725/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.

E. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1801

11. HIV protease inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1814
12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1816
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1816
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1816

1. Introduction point of interaction for the non-nucleoside reverse
transcriptase inhibitors (NNRTIs); (viii) integra-
The development of new anti-retroviral drugs is a tion of the proviral DNA into the host cell genome
dynamic process that is continuously fueled, at the ba- by the HIV integrase; (ix) proviral DNA expres-
sic level, by the identification of new molecular targets sion (transcription and transactivation); and (x)
for chemotherapeutic intervention, and, at the clini- HIV protease as target for both peptidomimetic and
cal level, by the problems (i.e. adherence, tolerability, non-peptidic inhibitors of the HIV protease. For a
toxicity, and virus-drug resistance) encountered with comprehensive review on new anti-HIV agents in
existing drugs. En route from their discovery as new preclinical or clinical development (see De Clercq,
anti-HIV entities to their eventual use for the treat- 2003).
ment of HIV infection, new anti-retroviral drugs have
to cross many hurdles, and at each point of the de-
velopmental process, emerging pitfalls have to be bal- 2. Cellular CD4 receptor down-modulators
anced against potential benefits at the end. This makes
it often unpredictable, or, at least unforeseeable, which The CD4 cell surface molecule serves as the pri-
compounds would make it all the way from the be- mary receptor for HIV infection of its target cells,
ginning till the end, the final approval for clinical and thus, drugs that target the CD4 receptor, thereby
use. inhibiting viral entry into the cells, may be consid-
Here, I will discuss a number of strategies for the ered an attractive approach towards prevention of
chemotherapy and prophylaxis of HIV infections, HIV infection. Cyclotriazadisulfonamide (CADA) (1)
based on new compounds that have recently entered was recently shown to inhibit HIV (as well as human
the anti-retroviral arena. Some of these compounds herpesvirus type 7) infection by down-modulation of
have just been identified as anti-HIV agents; others the cellular CD4 receptor (Vermeire et al., 2002). The
have already gone through the whole developmental antiviral activity of a large series of varying CADA
process to their final approval as anti-retroviral drugs. derivatives correlated closely with their ability to
This review on new trends and approaches towards down-modulate CD4 receptor expression (Vermeire
anti-retroviral drugs is not meant to be exhaustive et al., 2003). CADA is specific for the CD4 receptor;
but rather exemplary for the different strategies that it was found not to alter the expression of any other
could be pursued and those that have already proved cellular receptor (i.e. CXCR4, CCR5). Time course
to be successful. These strategies are focussed on experiments revealed that CADA in its mechanism
the following targets: (i) CD4 as the primary cell of action differs from that of aurintricarboxylic acid,
receptor for viral entry into the cell; (ii) gp120 as which binds directly to CD4, and phorbol myristate
the viral glycoprotein involved in virus adsorption to acetate, which activates protein kinase C (Vermeire
the cells; (iii) CXCR4 and CCR5 as the co-receptors et al., 2002): CADA is assumed to down-regulate CD4
for viral entry; (iv) gp41 as the viral glycoprotein expression at the (post)translational level (Vermeire
required for virus–cell fusion; substrate (dNTP) bind- et al., 2003). Further, pertaining to the promising
ing site of HIV reverse transcriptase, as point of character of CADA as an anti-HIV agent was the
interaction for the (v) nucleoside reverse transcrip- observation that it proved synergistic in its anti-HIV
tase inhibitors (NRTIs) and (vi) nucleotide reverse activity when combined with NRTIs (i.e. zidovudine,
transcriptase inhibitors (NtRTIs); (vii) non-substrate lamivudine, zalcitabine and abacavir), NtRTIs (i.e.
binding site of the HIV-1 reverse transcriptase, as tenofovir), NNRTIs (i.e. nevirapine and delavirdine),

.. (H2N)Leu Gly Lys Phe Ser Gln Thr Cys Tyr Asn Ser Ala Ile Gln Gly Ser Val Leu Thr Ser Thr Cys Glu Arg Thr Asn Gly Gly Tyr Asn Thr Ser Ser Ile Asp Leu Asn Ser Val Ile Glu Asn Val Asp Gly Ser Leu Lys Trp Gln Pro Ser Asn Phe Ile Glu Thr Cys Arg Asn Thr Gln Leu Ala Gly Ser Ser Glu Leu Ala Ala Glu Cys Lys Thr Arg Ala Gln Gln Phe Val Ser Thr Lys Ile Asn Leu Asp Asp His Ile Ala Asn Ile Asp Gly Thr Leu Lys Tyr Glu(COOH) Cyanovirin-N 2 with the viral envelope glycoprotein gp120 (Balzarini The aglycons of the glycopeptide antibiotics van- et al. Equally well qualifying as a potential microbicide N to prevent the transmission of HIV and acquired immunodeficiency syndrome is cyanovirin-N (2). the teicoplanin agly- ably correlated with an increasing number of mutated con (3). and the cyclams (i. they are endowed with a number of interesting properties that make them H3C CH2 CH3 primary candidate drugs to be considered for poten- O O tial use as microbicides for the prevention of the sex- S S ual transmission of HIV infection (Balzarini et al. the CXCR4 antagonist AMD3100. in particular. but not gp41: the vast against HIV-1. several amino acid drophobic nature. N-glycosylation sites (at the S or T residues). 2003). There was dinavir. Viral glycoprotein gp120 binders bound gp120 from target cells (Mori & Boyd. bi- tide). in. of the prototype compounds.. HIV-2 and Moloney murine sarcoma majority of these amino acid changes occurred at the virus at the lower micromolar concentration range.1802 E. AMD3100). O N N O 2003). The plant lectins represent a unique class of (GNA) and Hippeastrum hybrid (HHA) (Vermeire anti-HIV agents with an entirely novel HIV drug resis- et al. 2001). tant to GNA and HHA following repeated passages those containing substituents of a preferably hy- in the presence of the compounds. Cyanovirin-N exists as either a quasi-symmetric The above-mentioned plant lectins derived from two-domain monomer or a domain-swapped dimer. 1997). Cyclotriazadisulfonamide (CADA) Cyanovirin-N has a uniquely high affinity for gp120: it 1 impairs both CD4-dependent and -independent bind- ing of gp120 to the target cells. teicoplanin and eremomycin. comycin. glycosylation sites (Balzarini et al. when HIV-1 was made resis. and Time-of-addition experiments carried out with one the degree of resistance to the plant lectins invari. chicoric acid or T-20 (enfu- mannose-specific plant lectins from Galanthus nivalis virtide). GNA (Snowdrop) and HHA (Amaryllis) were shown as demonstrated by nuclear magnetic resonance and to interrupt the viral entry process by interfering crystallography (Botos & Wlodawer.. a 11 kDa protein originally isolated from the cyanobac- terium Nostoc ellipsosporum (Boyd et al. tance profile (Balzarini et al. saquinavir.e. In fact. 2003). it blocks CD4-induced binding of gp120 with CXCR4 and it dissociates 3. 2003).. 2003). amprenavir and ritonavir) as no cross-resistance of plant lectin-resistant viruses to well as the gp41 fusion inhibitor T-20 (enfuvir. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 PIs (protease inhibitors: lopinavir. other viral entry inhibitors such as dextran sulfate. 2003). were found to display activity changes were noted in gp120. nelfinavir.. have indicated that this type of compounds .

and. An orally bioavailable derivative of not interact with any other CXCR or CCR receptor AMD3100. such as AMD3100.. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1803 interferes with viral entry. individuals with dual (X4/R5) or mixed (X4 + R5) Various low molecular weight CXCR4 and CCR5 virus at base line. AMD3100 is now being pursued (in phase II clinical studies) for stem cell mobilization and 4. 2003). a significant enhancement of the while blood cells ably located at gp120) for these compounds still (WBC) counts in human volunteers (Hendrix et al. the HIV particles must interact.. respectively. the action of granulocyte-colony stimulating factor OH Cl Y = NH(CH2)3N(CH3)2 O O HO Cl O O O O H H H N N N NH2 Y N N N H H H O O O HO HO X OH HO O OH X = CH2NHAdam-2a Teicoplanin aglycon 3 (G-CSF). normal Proof-of-principle has been provided that CXCR4 T-cell expressed and secreted) and MIP-1␣ and -1␤ antagonists. Notably. 2002). E. AMD3100 at a dose as low as antagonists have been identified. remains to be resolved. strains (Schols et al. 2002). in HIV-infected X4 and X5 HIV strains.. in patients with multiple myeloma or non-Hodgkin lymphoma. CXCR4 normally AMD3100 functions as the receptor for the chemokine SDF-1 4 (stromal cell-derived factor). probably at the virus ad. 2003). Glycopeptide antibiotic agly. as this effect proved synergistic with sexual HIV transmission (Balzarini et al. are able to suppress (macrophage inflammatory proteins). following binding with the CD4 receptor. NH HN NH HN whereas CCR5 is the co-receptor for macrophage (M)-tropic (or X5) HIV strains. The binding site (prob. 2000). in vivo replication of X4 or dual-tropic X4/R5 HIV these chemokines inhibit infectivity of. During phase I sorption step. and CCR5 does so for RANTES (regulated upon activation. antagonization (De Clercq. it was then shown to mobilize hematopoietic con derivatives could be envisaged as potential lead stem cells from the bone marrow into the blood- compounds for application as microbicides against stream. To enter the cells.. CXCR4 and CCR5 antagonists transplantation. has recently been de- and blocks X4 HIV-1 replication through CXCR4 scribed that is as potent a CXCR4 antagonist and . and accordingly. the prototype of the 5 ␮g/(kg h) (continuous infusion) effected a complete CXCR4 antagonists being the bicyclam AMD3100 loss of X4 virus after 10 days of treatment (Schols (4): AMD3100 is truly specific for CXCR4: it does et al. with the CXCR4 or CCR5 co-receptor: CXCR4 is the NH N N HN co-receptor for T-lymphotropic (or X4) HIV strains. again through the viral envelope glycoprotein gp120. namely AMD070. it was found that AMD3100 caused added at 1–2 h post-infection. as their anti-HIV activity was lost if clinical studies.

at least in rats (Ichiyama et al. Br nium derivative TAK-779 (6) was the first non-peptidic N O molecule shown to block the replication of the M-tropic R5 HIV-1 strains (in the nanomolar con- centration range) by interaction with CCR5 (Baba et al. KRH-1636 appears to be SCH-C is able to achieve a 0. Also.. 2003). it may be 351125 various new. Claes. 1999). 2003. the quaternary ammo. seems to be endowed for 10 days to a number of HIV-1-infected adults with an anti-HIV activity profile similar to that of off therapy with other anti-retrovirals indicated that AMD3100. the MIP-1␣-elicited Ca2+ flux.. TAK-779 SCH-C (SCH 351125) 7 is not orally bioavailable and provokes irritation at the injection site. like AMD070. E913 specifically blocks the binding of et al. CCR5 an- orally bioavailable. 2001). Starting from SCH 2003).. it strongly inhibits the R5 HIV-1 strains. 2003). pursued as a candidate anti-HIV drug in clinical tri. The binding site for TAK-779 has been N O identified within the transmembrane (TM) helices 1. based Claes.. good oral bioavailability in rats.. 2000). Preliminary clinical data. on the oral administration of 25 mg SCH-C twice daily another CXCR4 antagonist. H N Cl- CH3 + H3C O N O CH3 TAK-779 6 Also SCH 351125 (SCH-C) (7) has potent activity in vitro against primary HIV-1 isolates using CCR5 and the replication of both laboratory and primary as their cell entry co-receptor. which means that. orally bioavailable. tant monocyte/macrophage-tropic R5 HIV-1 strains .e.. viral load (Reynes et al.. further research has led to the iden. 3 and 7 of CCR5 (Dragic et al. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 anti-HIV agent as AMD3100. (Strizki et al. additionally. dogs and monkeys) als (Schols. KRH-1636 (5). Schols.5–1. an orally bioavailable CCR5 tagonists is represented by the spirodiketopiperazine antagonist with potent anti-R5 HIV-1 activity (Iizawa E913 (8). Another class of low molecular weight CCR5 an- tification of TAK-220.1804 E. & De Clercq et al. MIP-1␣ to CCR5. as well as various multi-drug resis- replication of R5 HIV-1 in SCID-hu Thy/Liv mice. & Hatse et al.6-dimethyl pyrimidine amides. and that will be further and shows a favorable pharmacokinetic profile (i. containing symmetrical 2. O NH O N H2N NH KRH-1636 5 N Of the CCR5 antagonists. tagonists.. 2003). 2002).6-dimethyl ison- icotin amides and 2.. 2. N O were generated that showed equal or even enhanced H H N N affinity for the CCR5 receptor as compared to the par- N H ent compound (Palani et al.0 log10 reduction in duodenally absorbable.

3.0-fold reduction in plasma et al. From the spirodiketopiperazine class of compounds. Lynch. Willoughby et al. while exhibit- 3 ing much greater anti-HIV activity: this compound N 4 2 was also reported to block R5 HIV-1 replication in 5 HIV-1 (JRFL)-infected hu-PBM NOD-SCID mice N1 and to possess favorable oral bioavailability in rodents (Maeda et al.. 2002. 30 and 100 mg twice daily. 2002. At the onset of the fusion process. for 14 days) in HIV-infected adults. E.. Virus–cell fusion inhibitors O O The interaction of the X4 or R5 HIV-1 envelope N gp120 with the co-receptors CXCR4 or CCR5. FuzeonTM ) (10). O 1. primarily. a synthetic. thus providing proof-of-concept that HIV that reported for TAK-779 (Dragic et al. This site is overlapping yet distinct from HIV RNA. initi- ates the fusion of the viral envelope with the cellular E913 plasma membrane. 3. re- N spectively. highest dose (100 mg.. is followed by a spring-loaded action of N gp41 that then anchors through its amino terminus H O into the target cell membrane and. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1805 (Maeda et al. The general structure of this In an initial clinical trial carried out with T-20 at 1.. intra- The compound’s site of interaction with CCR5 has venously. 8 hydrophobic grooves on the surface of the coiled In addition to the afore-mentioned CCR5 antag.. scribed which possess oral bioavailability and/or po.. pentafuside. 36-amino acid peptide corresponding to residues tent anti-HIV activity (Hale et al. 2002. 2001). 10. 2001. near the extracellular surface. coil gp41 ectodomain become available for binding onists. in doing so. at the been mapped to a cavity.. AK602 was recently quoted as binding only partially to CCR5. 6 and 7 (Castonguay the fifteenth day a 1. pyrrolidine CCR5 receptor antagonists have been de. DP-178.3. 1.4-trisubstituted pyrrolidine series is depicted in 9. 2003). a wealth of. four doses (3.. fusion inhibitors are able to reduce virus replication .5–2. 2000). such as enfuvirtide (T-20. 2003). twice daily) T-20 achieved by formed by the TM helices 2. Lynch. precursor.3. 127–162 of gp41 or residues 643–678 of the gp160 & Gentry et al.4-trisubstituted with extraneous inhibitors.4-Trisubstituted pyrrolidine 9 O 5. & Hale et al. 2002).

2003). 2000). Meanwhile. have indicated that en.. However. Further analy.. Another. ences in potency were noted (Hazen & Lanier. 2003).. two phase III 6..e.932 Coviracil.. 2003). A once-daily com- plus optimized background (OB) therapy over OB bination therapy of emtricitabine with didanosine and therapy only (Katlama et al.e. Mutations G36D and lamivudine in vitro is dependent on the cell type. in- 11 cluding the prevention of maternal-infant transmission and the prevention of sexual transmission by topical What are the other NRTIs that are under (pre)clinical application as a microbicide (Ketas et al. and. 2003). respectively)) and seventh 2 . the emer. other anti-retrovirals. This inevitably leads to itabine has been considered an ideal drug candidate injection-site reactions including erythema. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 in vivo (Kilby et al. as experienced patients (Montaner et al. 2003). higher in vitro potency against HIV.3 -dideoxynucleoside analogue that has immunologic benefit (i. emtricitabine (2 . efavirenz has proven safe and both antivirally and im- sis of the virological responses in the TORO 1 and munologically effective for at least 24 weeks (Molina TORO 2 has ascertained that the virological responses et al. respectively. 2001) in that it shows synergism with tion. abacavir (ABC). in V38A within the GIV stretch at position 36-38 of primary cells (peripheral blood mononuclear cells and the amino terminal heptad motif of gp41 (Rimsky. incremental increases of (as on 2 July 2003) been officially approved for the CD4+ cell counts (44 and 275 cells/␮l. enfuvirtide (as well as the other viral entry inhibitors) should O be further evaluated for their clinical potential as Emtricitabine ((-)FTC. to enfuvirtide plus OB therapy was directly related to once-daily emtricitabine. and improved didanosine and efavirenz. conducted in North and South America (Lalezari Following zidovudine (AZT).. now marketed as EmtrivaTM ) (11) is the and 0.. Emtric- by subcutaneous injection. Emtricitabine can be following a 24-week treatment period. (−)FTC.781 log10 copies per ml. didanosine (ddI). indura. 1998). In follow-up studies through 60 weeks. in comparison with lamivudine. the so-called T-20 versus Optimized (NRTIs) Regimen Only Study 1 (TORO 1) and 2 (TORO 2). development and may eventually reach the anti-HIV . Nucleoside reverse transcriptase inhibitors clinical studies. previously referred to as benefit (i. (Richman. and this may allow virus escape from drug (Heil et al. incremental viral load reduction (0.. 2003) and Europe and Australia (Lazzarin citabine (ddC). combined with once-daily the activity of the background regimen. respectively)) treatment of HIV infections. ing). equally in. the gence of virus-drug resistance should be continu. excellent tolerability. EmtrivaTM) inhibitors of HIV-1 replication in several settings. zal- et al. 2003)..3 -dideoxy-3 -thia- fuvirtide (T-20) provided significant anti-retroviral 5-fluorocytidine. and nodules and cysts.. lamivudine (3TC) and et al. However. & Matthews. 2001) for long-term clinical findings.. Follow-up conveniently administered as a once-daily dose of studies over 48 weeks have confirmed the 24-week 200 mg (Rousseau et al. As for all specific anti-HIV drugs. a long evitable problem is the production cost for a 5000 Da intracellular half-life (supporting the once-daily dos- molecular mass peptide such as enfuvirtide (Bray. compared to twice-daily stavudine and once-daily Enfuvirtide has to be administered twice daily didanosine and efavirenz (Raffi et al. given O N the fact that T-20 (as well as SCH-C and RANTES) inhibit the replication of different CCR5-using pri- HO S mary viral isolates in multiple cell types. monocyte-derived macrophages) no significant differ- Shugars. Even NH2 enfuvirtide-insensitive HIV-1 variants may exist in an F N enfuvirtide-naı̈ve population. stavudine (d4T). tations seem to emerge promptly in patients upon monotherapy with enfuvirtide (Wei et al. relative anti-HIV-1 potency of emtricitabine and ously and carefully monitored.1806 E. 2002). 4–10-fold 2003). 1998) but also other mu. thus supporting the efficacy of enfuvirtide use in HIV-1-infected individuals. 2003). demonstrated durable responses were observed in less advanced and less and superior virologic efficacy and tolerability.

Nucleotide reverse transcriptase inhibitors N (NtRTIs) O N In contrast to the nucleoside reverse transcriptase HO inhibitors (NRTIs). Claire. however. Borroto-Esoda.7-fold resistance to RVT in vitro where standard nucleoside therapy failed. Also drug-resistant HIV-1 iso- rying the Q151M mutation (Geleziunas et al. the most advanced is amdoxovir and PMPApp. ReversetTM ). 2003)...3 -dideoxynucleo. dovudine (M41L/D67N/K70R/T215Y/K219Q) and boring mutations in the reverse transcriptase gene lamivudine (M184V) (Furman et al. RVT may be useful as a once-a-day component for the treatment O N N NH2 of NRTI-experienced patients (Murphy et al.. RVT effected O a viral load reduction below the detection limit for Amdoxovir (DAPD) both the NL4-3 and 3TC-resistant M184V HIV-1 13 strains (Stoddart. 2003). respectively). 12 and. Qi. remained (Geleziunas et al. only need two phosphorylation steps Among the new purine-based 2 . St. the nucleotide reverse transcript- O ase inhibitors (NtRTIs). therefore. 2002). the latter then serve as ((−)-␤-d-2.. & Schinazi. RVT itself selects for the K65R mutation the 69 double codon insertion SS or SG) from patients which confers 5. NH2 F 7.3 -didehydro-2 .. 2001). DAPD is converted by adenosine deaminase strate dATP) in the reverse transcriptase reaction. 2000) and its 5-fluoro-substituted counter. 2003). E. lates (including multi-drug resistance variants with In addition... 2002). DXG part FdOTC (Racivir® ) (Otto et al. 1986).. BCH-10652) (Stoddart phorylated intracellularly to DXG 5 -triphosphate. and 5 -triphosphate (DXG-TP) acts as an alternative sub- ␤-d-2 . ... corresponds to the 5-fluoro-substituted derivative of Intracellular DXG-TP levels have been demon- ␤-d-d4C (␤-d-2 . 2002). HO In the SCID-hu Thy/Liv mouse model. 2001). 2002). to be converted to the active metabolites (PMEApp side analogues. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1807 drug market? These include (±)2 -deoxy-3 . & Furman. Feng. ReversetTM (RVT) (12) (Jeffrey. 2002). strated in peripheral blood mononuclear cells from a compound that was already described in 1986 HIV-infected patients receiving oral DAPD (500 mg as a potent and selective anti-HIV agent (Balzarini twice daily) (Kewn et al. to dioxolane guanine (DXG) which is then phos- oxa-4 -thiocytidine (dOTC. A phase I clinical study has demonstrated NH2 that the desired plasma concentrations of RVT can be N N easily achieved with an oral dose of 50 mg.3–8. It should be noted that ␤-d-d4FC proven active against HIV-1 mutants resistant to zi- (RVT) retains activity against HIV isolates har. it seems less potent against and Q151M mutations (Painter. Anderson. Bozeman.. 2002).. 2003). RVT is readily converted susceptible to DXG.6-diaminopurine dioxolane (DAPD)) alternative substrates (with respect the natural sub- (13). et al. number of other anti-HIV agents (Erickson-Viitanen et al. 2003). but has that confer resistance to 3TC or AZT (Schinazi decreased activity against viruses carrying the K65R et al.3 -dideoxy-5-fluorocytidine strate/inhibitor of the HIV-1 reverse transcriptase (␤-d-d4FC. DAPD/DXG has et al.3 -didehydro-2 . resistance to DXG was observed to its 5’-triphosphate in human peripheral blood only for recombinant isolates harboring the K65R and mononuclear cells and interacts synergistically with a Q151M double mutation (Mewshaw et al. the active metabolite (Furman et al. Feng. particularly those car. such as adefovir (9-(2-phos- phonylmethoxy-ethyl)adenine (PMEA)) and tenofovir ((R)-9-(2-phosphonylmethoxypropyl)adenine (PMP- β-D-d4FC (ReversetTM) A)) are already equipped with a phosphonate group.3 -dideoxycytidine). & multi-NRTI-resistant viruses.

pancreatitis) associated with mitochondrial Adefovir dipivoxil (HepseraTM) dysfunction through week 96 were markedly lower in 14 the TDF arm than in the d4T arm. 2003). 2003): both treatment groups showed a mean re- and HIV infections. subse- proxil (bis(isopropyloxycarbonyloxymethyl)-PMPA) quently. 2003). Whereas at the present time. emtricitabine observed HIV-1 RNA responses (Margot.. are not only active against HIV but also hepatitis From an ongoing 3-year. lactic O acidosis. & Miller. double-blind B virus (HBV). duction in HIV RNA load of 3. 2002) and. Adding TDF study is still ongoing. showed a similar renal safety profile. 600 anti-retroviral-naı̈ve patients with HIV infections. 48 weeks of to examine in the future a regimen consisting of TDF which included suboptimal doses of TDF. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 where. as HBV clinical trial being conducted at 81 sites in the US. and amdoxovir. as their oral efavirenz to a regimen of d4T. Akin of the patients). there was + (−)FTC + efavirenz. 3TC and efavirenz in prodrug forms. the 96-week data were divulged (Staszewski fumarate (VireadTM ) (15). mutation (K65R) associated with TDF therapy (3% rily as chain terminators (De Clercq. both the d4T arm and TDF arm showed a similar.1808 E. Cheng. HepseraTM ) (14) and tenofovir diso. lipid abnormalities (increase in (CH3)3C C O CH2 O O triglyceride and cholesterol levels) were significantly P O lower in the TDF arm than in the d4T arm. most efficient drug regimen.. Thus. randomized. Although this scribed as a once-daily dose of 300 mg. Also the (CH3)3C C O CH2 O toxicities (peripheral neuropathy. consistent with the durability of the to the NRTIs such as lamivudine. while both arms NH2 N N COOH N N O (CH3)2CH O C O CH2 O O P O HOOC (CH3)2CH O C O CH2 O O CH3 Tenofovir disoproxil fumarate (VireadTM) 15 Tenofovir disoproxil fumarate (TDF) is pre. the sistance mutations resulted in significant and durable combination of TDF + 3TC + efavirenz looks like a reductions in HIV-1 RNA levels through week 96. adefovir dipivoxil (bis(pivaloyloxy. for the treatment of HBV et al. comparing the efficacy is quite similar to that of HIV. for example. the NtRTIs adefovir and tenofovir McGowan. and safety of a treatment regimen of TDF. respectively. 95% NH2 of the patients in the TDF arm compared to 91 in the N d4T arm had reductions in HIV RNA load to below N 50 copies per ml after 96 weeks. lipodystrophy. they act obligato. However. upon their incorporation. in comparison infrequent development of the reverse transcriptase with a regimen containing AZT + 3TC + efavirenz. high virological N N O response. it would seem worthwhile through 96 weeks of TDF therapy. Isaacson. . which is not surprising. uses for its replication a reverse transcriptase that Europe and South America.09 log10 copies per ml (base line: 4. the 48-week data (Staszewski et al. the ad interim results point to (300 mg) to existing anti-retroviral therapy for highly a similar efficiency but better safety profile of TDF treatment-experienced patients with preexisting re.9 log10 copies/ml) after 48 weeks. 3TC and fovir have been officially approved. as compared to d4T. methyl)-PMEA. Adefovir and teno.

therefore. Capravirine (17) is such a compound which patients coinfected with HIV and 3TC-resistant HBV retained activity against HIV-1 strains carrying the was not associated with the emergence of HIV or K103N mutation in their reverse transcriptase (Ren HBV specific resistance mutation (Marcelin et al. The “first generation” NNRTIs are notorious for Another indication for the clinical use of tenofovir rapidly eliciting virus drug resistance. Three NNRTIs (i. but its of low-dose TDF did not protect infant macaques development has in the mean time been discontinued. non-substrate binding) H3C site of the reverse transcriptase. 1997). These attempts have led to the Tubiana.. 2002). in a monotherapy lated in replens gel (Balzarini et al. but have 8. especially when dipivoxil fumarate is (lamivudine-resistant) chronic used singly (as monotherapy). & Berg. capable was concluded that systemic administration of potent of reducing the infectivity of HIV-1 virions (Borkow antiviral compounds such as tenofovir may be the et al. Emivirine (MKC-442) (Szczech sion of through breast-feeding.. attempts have been made to develop “second patients carrying either wild-type or 3TC-resistant generation” NNRTIs that are resilient to such drug (YMDD variant (rt M204I/V)) HBV (Benhamou. a response that was C Cl considered as robust as that observed with ritonavir N H CH3 monotherapy (Louie et al.5 log10 reduction in HIV-1 RNA levels follow. Van Bömmel. and. 2003. In fact. candidate microbicide (virucide). S ing a 3-week treatment course.e. AG1549) formally licensed for clinical use in the treatment of 17 . 2000) should have been the fourth one. TDF treatment for 12 months in tions. against multiple oral exposures of simian immunod.. indeed resilient to the K103N and/or Y181C muta- 2003). allosteric (i. for topical trial with TDF in 10 chronically HIV-1-infected application to prevent the sexual transmission of HIV. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1809 Although in an animal model for HIV transmis. compounds that are specifically inhibitory Cl S N O NH2 to the replication of HIV-1 (and not any other retro- viruses such as HIV-2 or SIV) and that are targeted N at a specific. clinical trials. The most common hepatitis B in HIV/HBV-coinfected patients. anti-retroviral-naı̈ve individuals. Capravirine has proceeded to phase II/III 2003). the drug achieved a 1. delavirdine and efavirenz have so far been Capravirine (S-1153. O 1998).. 1998). Cl CH3 nevirapine. when formu- mission via breast-feeding. the thiocarboxanilide UC-781 (16) eficiency virus (SIV) (Van Rompay et al.... Ristig identification of a number of compounds that are et al. Hopf.. 2002. which were temporarily put on hold (due to animal toxicity studies showing vasculitis in dogs after 48 weeks of drug administration). There- in reducing HBV DNA levels in HIV/HBV-coinfected fore. (NNRTIs) N More than 30 structurally different classes of com- pounds have been identified as NNRTIs (De Clercq. Schernick.. i. HIV-1 infections. It would now seem OCH2CH C worth examining whether the use of TDF in the initial O CH3 CH3 treatment of chronically HIV-1-infected individuals Thiocarboxanilide UC-781 may also reduce the risk of HIV transmission from 16 these individuals to their partners (sexually) or from mother to child (perinatally). et al. E. Another NNRTI. viz. 2003). seems to be an ideal best chemoprophylactic strategy to reduce HIV trans. & Thibault. Several mutations occurring in the clinical setting following studies have demonstrated that TDF is very effective the use of NNRTIs are K103N and Y181C. Noteworthy.e. 2000). topical administration et al. it has been recognized as a retrovirucidal agent. Non-nucleoside reverse transcriptase inhibitors recently been resumed. Nunez et al.e. resistance mutations. 2002.

furthermore. 2002). administered orally once-daily at a dose of 100 mg. a viral load reduction of 1. .. sug. HIV integrase inhibitors gesting that DPC 083 was active against viral variants with resistance to currently available NNRTIs (Ruiz Integration of the proviral DNA into host cell chro- et al. and. about 40–50% of the subjects 19 had HIV-1 RNA levels below 400 copies per ml. 2000). & Lange. 18 An example from the first class of compounds is l-chicoric acid (20). The long plasma half-life of the com- pound supports once-daily (or even less frequent) O N NH dosing (Corbett et al. a derivative of efavirenz. cant antiviral potency (i. after 1 week of grase (Pluymers et al. twice It was later shown that the G140S mutation not only daily for 7 days in treatment-experienced patients confers resistance to l-chicoric acid but also to the with highly NNRTI-resistant virus and failing on an diketo acid L-731.. TMC 125 (etravirine) (19) is an molecular target for the action of l-chicoric acid.5–2. 2002).9 log10 ) (Gazzard et al. HIV strains resistant Weverling. At 16 weeks. mosomal DNA is an essential step in the viral repli- cation cycle.. mu- a similar initial rate of decline of plasma HIV-1 RNA tations were found in the viral envelope glycoprotein levels as seen with a five-drug regimen (Sankatsing. has marked N N activity against HIV-1 strains with various mutations in their reverse transcriptase (L100I. in patients N who had failed on the current NNRTIs and harbored Br NNRTI-resistant mutations. effected. When TMC 125 resistant to l-chicoric acid (King & Robinson. Y188L.. but not in the integrase. after 8 weeks of NH2 treatment. and time-of-addition experiments this antiviral potency is sustained and whether TMC further confirmed that the primary site of interaction 125 does not lead to untoward side effects or engen. for l-chicoric acid is the virus adsorption stage rather ders drug-resistant mutations on its own. 2002). attenuates NNRTI-containing regimen. G140S mutation appeared to be as sensitive to the in- monotherapy with TMC 125 in anti-retroviral-naı̈ve hibitory effect of l-chicoric acid as the wild-type inte- HIV-1-infected individuals effected. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 DPC 083 (18). the catalytic activity of the enzyme (King et al. HIV-1 integrase carrying the 0. 9. investigational NNRTI with potent activity against since a single amino acid substitution (G140S) in the HIV-1 strains resistant to the currently available integrase rendered the corresponding HIV-1 mutant NNRTIs (Andries et al. 2000). however. and. 2002). 2003). at a dose of 900 mg.. than the integrase (Pluymers et al. In another study. 1999). it demonstrated signifi. as there is no cellular homologue for this enzyme. a 1.988.. 2003)). 1998). Y181C.28 log10 (Ruiz et etravirine (TMC125) al. to polyanionic compounds showed cross-resistance Longer-term studies seem warranted to verify whether to l-chicoric acid.. viral load reduction up to In our hands. DPC 083... Prins. Integrase was identified as the Like DPC 083. K103N.1810 E.0 log10 reduction of viral load. was administered orally. it has been considered an attractive tar- F3C get for HIV therapeutics. Numerous small-molecule Cl HIV-1 integrase inhibitors have been described.e. gp120. Upon repeated passages treatment. This process is mediated by the viral integrase. K103N + L100I and K103N + Y181C) that make them resistant to the current NNRTIs (Corbett et al. 2000). van’t Klooster. 2000). the NH two most predominant classes of inhibitors being the catechol-containing hydroxylated aromatics and the N O H diketo acid-containing aromatics (for a recent review DPC083 (see Dayam & Neamati. with of the virus in the presence of l-chicoric acid.

1999). 2002). L-708. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1811 OOC COO HO OH O O HO OH O O L-chicoric acid 20 The structure of the HIV-1 integrase core domain complexed with the inhibitor 5CITEP (1-(5-chloroin. without loss Fujishita. the highest selectivity thus far confirmed by quantitative Alu-PCR (Pluymers et al. The mechanism integrase (Fikkert et al. thus achieving a therapeutic index of action for the diketo acids in cell culture could be almost one thousand. of the integrase. in the Sato. Fujishita.906 and cross-resistance to an interaction between the carboxylate group of the the diketo acid derivative S-1360. three mutations. The triple-mutant of action of the diketo acids (i.988.906 could be postponed.988 were also found S-1360 (23) actually represents the first integrase to inhibit HIV-1 replication in cell culture. till 7 h after infection. inhibitor to reach clinical studies (Yoshinaga. such as L-708. and addi. another other compounds and metal ion(s) in the active site integrase inhibitor type (Fikkert et al. & Fujiwara. resulting in a functional sequestra- tion of these critical metal cofactors (Grobler et al. The diketo acid derivatives L-708.. but remained fully diketo acids or the isosteric heterocycle in the two sensitive to the pyranodipyrimidine V-165. 2002). several additional L-708. E. 2003).906 21 4-aryl-2. & Fujiwara.. 2002). S-1360 is orally 2002). while its CC50 would That proviral DNA integration is indeed the target of be 110 ␮M. tion of L-708.4-dioxobutanoic acid derivatives have been .e. i. cation at an EC50 of 140 nM..e.906 led to the successive accumulation of HIV-infected subjects have been initiated (Yoshinaga. the HIV-1 integrase at an IC50 of 20 nM. O dol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone) C has been described as a platform for the structure-based N O design of novel HIV-1 integrase inhibitors (Goldgur O O et al. HIV-1 repli- incides with (the onset of) proviral DNA integration. S-1360 would inhibit of activity. 5CITEP and S-1360 may be based on susceptibility to L-708..988 (22) as inhibitors of the integrase-mediated F strand transfer reaction (which is responsible for the L-731.. This was followed by the description of a number of diketo acids.988 22 covalent linkage of the viral DNA 3’ ends to the cellular DNA (Hazuda et al. F H N N O O N O O OH C S-1360 O O 23 O O Starting from L-731.988). 2003).906 and virus (T66I/L74M/S230R) showed a 10-fold reduced L-731.906 and L-731. 2000). Repeated passages of HIV-1 in the presence bioavailable and phase I/II studies with S-1360 in of L-708..906 (21) and L-731. Sato. reported for an integrase inhibitor. T66I. L74M and S230R. a time point that co.

since the mutations (T66I. 1997). A to the mechanism of action proposed for HIV-1 inte. through interference with the transcrip- Recently.4-dehydro-4-phenyl-1-piperidinyl)-1. revealed that the peptoid CGP 64222 owes a conclusion that was corroborated by quantitative its anti-HIV activity in cell culture primarily to an Alu-PCR. 2003). from L-731. however. The [7-(3. consequently to its binding to the 2003). 1997). temacrazine dipyrimidine (V-165) (24) inhi-bited the replication [1. A close correlation was found between the hibitor (Chao et al.6-dihydroxy-5H-pyrano[2. new azido-containing aryl diketo acids have been described as HIV-1 integrase in. Okamoto. 2000). capping enzyme (Chiu et al. flavopiridol. at the molecular level. number of compounds have been reported to inhibit grase inhibitors of the same structural class (Grobler HIV-1 replication in both acutely and chronically et al. infected cells. . the mechanism interaction with CXCR4. a 9-mer peptoid.1812 E. a natural product anti-HIV activity observed in cell culture and the from Streptomyces (Baba. namely that of the to inhibition of Tat (or other transactivators): K37 5H-pyrano[2. structurally assays.4-dihydro- most potent congener of this series.988 a novel diketo acid.. 10. 2000)..5-d’]dipyrimidines (PDPs).. 6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline- 2. inhibitory activity in the integrase strand transfer 1999). on Tat-dependent trans- Pyranodipyrimidine (PDP) (V-165) activation and HIV replication (Daelemans et al. 2002).3-d:-6. 3-carboxylic acid (Okamoto et al.3-d:-6.5-d ]. a cyclin-dependent kinase (CdK) in- 2002)... such as neplanocin A and SH N O N SH 3-deazaneplanocin A (25). At the transcriptional level.. which is 14-fold aminopropyl)piperazine] (Turpin et al.. 2002). & Takeuchi. the metal-dependent motor by the viral Tat (trans-activating) protein behavior of this RNase H inhibitor being analogous (Daelemans. ulated by Tat. tion process that could at least partially be attributed grase inhibitors was identified. HIV gene expression hibitors capable of conferring antiviral protection may be inhibited by compounds that interact with in HIV-infected cells (Zhang et al. the diketo acids. 24 1997).. L74M It has been recently demonstrated that the and S230R) that engendered resistance to the diketo co-transcriptional capping of HIV mRNA is stim- acids did not do so towards V-165 (Fikkert et al. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 described as HIV-1 integrase inhibitors (Wai et al. Greater specificity. 5-(4-nitrophenyl). below the cytotoxicity threshold (Pannecouque et al. the co-receptor for X4 HIV of action of V-165 must be different from that of strains (Daelemans et al. however. Yet. EM2487. In. may be acid.9 ␮M. has been derived that binds to and inhibits the expected from those compounds that specifically RNase H (p15) domain of the HIV-1 reverse transcrip.4-bis(3-(6-oxo-6H-v-triazolo[4.1-de]acridin-5-yl- of HIV-1 at an EC50 of 8.8-dithiol-4. cellular factors (such as NF-␬B) that bind to the terestingly. They also offer an explanation for N N the inhibitory effects of S-adenosylhomocysteine hydrolase inhibitors. & De Clercq. Transcription (transactivation) inhibitors 2000). and CGP 64222. LTR promotor and that are needed for basal-level 4-[5-(benzoylamino)thien-2-yl]-2. Time-of-addition experiments indicated that reminiscent of the amino acid 48-56 sequence RKKR- V-165 interfered with the viral replication cycle at a RQRRR of Tat (Hamy et al. 1999). 2003). an entirely new class of HIV inte.. Vandamme.5.. 2000). 1998). time point coinciding with proviral DNA integration..4-dioxobutanoic transcription. inhibit the transactivation of the HIV LTR pro- tase (Shaw-Reid et al... These findings implicate capping as an elongation checkpoint critical to HIV gene expression and thus corroborate earlier NO2 observations that S-adenosylmethionine-dependent methylations (involved in the capping process) play an important role in the Tat-dependent trans- OH OH activation of transcription from LTR (Daelemans et al. Further analysis.. Also.

Pannecouque. HN tially spliced) HIV mRNA. 2003). Aryl 25 R N Y: SH. JPL-133. Pannecouque. & Balzarini. can ex- small-molecular. Apart from its potential dine oxides behave as typical NNRTIs: the most as a lead antiviral compound. it leads to the NNRTI-characteristic mutations in the HIV-1 reverse transcriptase: K103N. Y181C and Y188H (Stevens. active congener from this series. 2003). This process can be blocked by a been described which. 2003). JPL-32 also inhibited PKF 050-638 26 the Tat-mediated HIV-1 mRNA transcription from HIV-1 LTR. formation and. PKF may be a use. like the NAIMS. OH OH X = N: Neplanocin A X1.. X2: Halogen.weight molecule. structurally analogous to capravirine level. PKF 050-638 (26). a set of pyridine oxide derivatives (pro- so as to export viral mRNA from the nucleus to totypes JPL-32. For other pyridine ox- ides such as JPL-32 and JPL-88. 27 pression of viral proteins (Rev). N-aminoimidazoles (NAIMS) port is promoted by the HIV-1 regulator of ex. this mRNA has to be transported from the nucleus into the cytoplasm in order to be translated to viral proteins. AG1549) and of the general formula 27. Pannecouque. ity index of approximately 760 in cell culture. a series of N-aminoimidazole deriva. E138K. 2002). & Balzarini. JPL-88 and JPL-133) (28) have the cytoplasm. 2003. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1813 NH2 (S-1153. and (iii) combi- nation of both type (i) and type (ii) of action (Lagoja OH et al. V108I. Pannecouque. E. The mode of action of JPL-32 appeared O O to be reminiscent of that of K-37 in that JPL-32. De Cl Clercq. This ex. 2002). hence. thus clearly indicating that its target of Recently. Some of the pyri- (Daelemans et al. De which specifically inhibits the CRM1-NES complex Clercq. De Clercq. or early transcription (transactivation) step. Nuclear export of Rev is mediated by its leucine-rich nuclear export signal (NES). & Balzarini. action is located at the transcription transactivation tives (NAIMS). H Y N X2 X1 Following transcription of the unspliced (or par. has an ful tool in exploring CRM1-mediated nuclear export EC50 of 0. . like K-37.. time-of-addition NH2 experiments revealed a post-integration step in the HIV replicative cycle as the most likely target of ac- N N tion (Stevens. The as yet unidentified target may well correspond to an immediate post-integration. NES uses the export factor CRM1 Similarly. & Balzarini. was active in both acutely and chron- CH3 ically HIV-1-infected cells. Alkyl X = CH: 3-Deazaneplanocin A R: Alkyl. hibit a dual behavior (Stevens. Rev-mediated nuclear export De Clercq.. (ii) X N an as yet unidentified target of action. N 2003). Stevens.05 ␮g/ml against HIV-1 and a selectiv- pathways. have been found to inhibit HIV replication through N N one of the following types of interaction: (i) the clas- sical NNRTI type of action (Lagoja et al.

p7.1814 E. remained sensitive to saquinavir. Conversely. 54V/L. In highly anti-retroviral-experienced patients. and atazanavir. ritonavir. with a favorable pharmacoki. and amprenavir-resistant HIV-1 strains O O remained sensitive to BMS-232632. 84V. - R1 Z S R2 O O - N+ Y1 Y1 H H H R2 Y2 H H H Y3 H H H Y4 Y2 Y4 H H Cl Y3 Pyridine oxides JPL-32. N The aza-dipeptide analogue atazanavir (29). -88 and –133 28 11. O N N H H saquinavir-. while no single substitution or com- of infectious virus particles. maturation and infectivity of the progeny virions. 71V/T/I. and integrase (p32)).0-fold reduction in susceptibility). All protease inhibitors bination of substitutions was predictive of atazanavir (PIs) that have been licensed for the treatment of HIV resistance (>3. but showed various levels of cross-resistance to nelfinavir. selected 29 upon repeated passage of the virus in the presence of the compound. p1) and and -resistant clinical isolates identified a strong cor- functional proteins (protease (p11). which makes these compounds peptidomimetic but non-scissile substrate analogues for the HIV protease. an (Colonno. Nelfinavir-. 24I. 46I/L. i. share related strongly with loss of atazanavir susceptibility the same structural determinant or scaffold. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 JPL-32 JPL-88 JPL-133 X3 X1 Cl CH3 CH3 X2 Cl H H X4 X2 X3 Cl CH3 H X4 Cl H CH3 X5 Cl CH3 H X5 X1 O Z H H H R1 O . 2000). 33I/F/V. once-daily atazanavir/saquinavir showed comparable . amprenavir.. 73C/S/T/A. while indinavir- and ritonavir-resistant viruses showed 6–9-fold changes in sensitivity to BMS-232632. and decreased susceptibil- of the viral replication cycle and prevent formation ity to atazanavir. 20R/M/I. 48V. Limoli. hydroxyethylene (instead of the normal peptidic) bond. 63P. namely saquinavir. H H N N N O netic profile allowing once-daily dosing. presence of at least five of these substitutions cor- nelfinavir. the infections. Thiry. indinavir. reverse transcrip- relation between the presence of amino acid changes tase (p66/p51). distinct from O OH O that of the other PIs. ritonavir and amprenavir (Gong et al. 2003). indinavir. combines a favorable resistance profile. p24. HIV 36I/L/V. protease inhibitors will interfere with this late stage 82A/F/S/T. I84V) virus. ReyatazTM) BMS-232632-resistant (N88S. HIV protease inhibitors Atazanavir (BMS-232632) appeared to have a resis- The HIV protease is responsible for the cleavage tance profile that is distinct from that of the other PIs: of the gag and gag-pol precursor polyproteins to the analysis of the genotype profiles of 943 PI-susceptible structural proteins (p17.e. Atazanavir (BMS-232632. p6. & Parkin. thereby securing at specific residues (10I/V/F. the latest and seventh PI to be approved for clinical use. p2. and 90M). lopinavir.

has an excellent activity profile against N H HIV variants that are highly resistant to current OH N F PIs (de Béthune et al. 2002). which. a struc. and sustained el. Tipranavir retained marked activity against HIV-1 iso- tional effect on body fat distribution at 48 weeks. emerged. shows little cross-resistance with the pep- evations in these parameters of a magnitude that tidomimetic PIs. 31 .4 log10 not (Yoshimura et al. acid residues D29 and D30. as compared mutations per isolate. and only 2% had more than dovudine and lamivudine). 2003). fasting LDL metic inhibitor of the HIV protease (Poppe et al. E. it might therefore patterns of central adiposity characteristic for be useful in drug combination regimens with other the development of lipodistrophy (Jemsek et al. TMC 114. 2003). CH3 fected with HIV-1: once-daily atazanavir rapidly and UIC-94003 (TMC-126) durably suppressed HIV RNA levels and durably 30 increased CD4 cell counts. In a study of pa- containing a bis-tetrahydrofuranyl urethane and tients experiencing virological failure on their second 4-methoxybenzenesulfonamide (and thus structurally PI-containing regimen. mutants carrying a sistance mutations versus −2. TMC 126 (UIC-94003) is a peptidomimetic PI Sabo. produced a comparable and propor. cholesterol. Mod.. subjects were randomized related to amprenavir): it was reported to be extremely to receive tipranavir (500 mg or 1000 mg)/ritonavir potent against a wide spectrum of HIV-1 strains (100 mg) twice daily: at 48 weeks in the lower-dose (EC50 : 0.. Tipranavir (PNU-140690) (31) is a non-peptidomi- evant increases in total cholesterol. Of 105 clinical HIV-1 isolates with suggests they are clinically relevant (Sanne. when given both as H CH3 OCH3 OH monotherapy and in combination with didanosine and stavudine in anti-retroviral-naı̈ve subjects in. O In another study. with >5 PI-associated mutations (Schwartz et al. A28S. Further clinical investigations with tipranavir with the main chain of the protease active-site amino are in progress... pected. more than 10-fold reduced susceptibility to three or Squires. the mean change in HIV RNA was −2. patients. anti-retroviral agents for patients who already failed 2003). 1998). to tipranavir (Larder et al. 8% to efavirenz (both combined with fixed-dose zi. or fasting triglycerides. & Schnittman. drug levels can be markedly increased (“boosted”) tural analogue of TMC 126 (UIC-94003) (30). once-daily atazanavir (200 mg. and this may be important for its potency.3–0. Clinical studies with F F TMC 114 have been initiated (Van Der Geest et al. 1997. in anti-retroviral-naı̈ve 10-fold resistance. O O O S O 400 mg or 500 mg) was compared with nelfinavir O N N (750 mg three times daily). four of the peptidomimetic PIs and an average of 6 ies have ascertained that atazanavir. Galitz. atazanavir was not associated with clinically rel. by co-administration with ritonavir (McCallister.. Tipranavir (PNU-140690) 2001). 2002). 2000). Turner et al. eling studies revealed close contact of UIC-94003 2002). Tipranavir Under clinical development is TMC 114. in comparison. Upon passage of HIV-1 copies per ml for subjects with ≤5 PI-associated re- in the presence of UIC-94003. Piliero. on other PI-containing drug regimens. Other stud.. particularly against drug-resistant HIV-1 O O variants (Yoshimura et al. both in combination with two NRTIs (Haas et al. as could be ex- nelfinavir led to prompt. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 1815 efficacy to twice-daily ritonavir/saquinavir.. had 4–10-fold resistance. Thiry..2 log10 copies per ml novel active-site mutation.. 90% were fully susceptible.5 nM). lates derived from patients with multidrug resistance consistent with weight gain and not with the to other PIs (Rusconi et al. & Mayers.. marked. 2001). 2000). 2002). like O S O TMC 126.. whether resistant to other PIs or group. different from that of the other PIs. through 48 weeks.

& Takeuchi. cohorts with alternative combination regimens. such as the pyranodipyrimidine V-165. J. Canada. studies have indicated that novel combinations of Balzarini.. AMD070) and CCR5 antagonists (i. nonpeptide CCR5 available. plant lectins. 12.. 2755–2764. N. & Parniak. the NtRTI teno. proxil fumarate. as in the past. transcription transactivation Proceedings of the Abstracts of the 40th Interscience Conference event that remains subject of further investigation. et al.. combinations should be carefully monitored for possi- fovir disoproxil fumarate (VireadTM ) and the PI ble pharmacokinetic drug-drug interactions. still augment the potency of HAART by as much as Y. which for atazanavir (ReyatazTM ). new NRTIs such as amdoxovir. J. (1998). S. (synergistic) potency and reduced risk of virus-drug D. (1999). C. while at the cellular level... a novel substance regimens provide a virological efficacy that is at produced by a Streptomyces species. may Balzarini. J... human immunodeficiency virus type 1 replication in acutely ized clinical trials have shown that these once-a-day and chronically infected cells by EM2487. as Proceedings of National Academy of Sciences of United States well as for some of the “older” compounds such of America. et al. et al. M. especially in terms of enhanced Balzarini.e. SCH-C). K. V. A major breakthrough at the clinical stage is that Baba.e. and new PIs such as tipranavir. R165335-TMC125. Pauwels. triple)-drug combination regi- mens. O. Inhibition of as efavirenz and didanosine.. Mannose-specific plant 2003).. made towards the chemotherapy of HIV infections. Is there still room for improvement? Recent immunodeficiency virus. E.. Journal of Medical Chemistry.. A small-molecule. de Béthune.3 - . Verbeken.. Hatse. gp120 binders (i. 1129–1138. P. may be expected from HTLV-III/LAV activity of 2 . Potent and selective anti- resistance development. as compared to matched Immunodeficiency Syndrome. & Janssen. new NNRTIs such as etravirine (TMC Acknowledgements 125)... Pannecouque. J. Azijn. M. Antiretroviral activity of semisynthetic derivatives of It is evident that in the future. cyclotri- azadisulfonamides). a classes of compounds (i. & Kang. S. or still remain to be. Printsevskaya.. 96. E. glycopeptide antibiotics. H. M. De Clercq... Baba. De Clercq / The International Journal of Biochemistry & Cell Biology 36 (2004) 1800–1822 12. Okamoto. for the new compounds tenofovir diso. antagonist with highly potent and selective anti-HIV-1 activity. in vivo drug NRTI emtricitabine (EmtrivaTM ). Pavlov. J. M. (2003). (2000).. 43. the greatest benefit. elucidated) have been identified: CD4 down-modulators (i. N-aminoimidazoles and novel non nucleoside reverse transcriptase inhibitor (NNRTI) pyridine oxide derivatives) which seem to interfere with nanomolar activity against NNRTI resistant HIV strains. Cooney. In addition.. Submitted for publication. E. et al.. J. De Clercq. anti-retroviral therapy” (HAART) (Ena & Pasquau.. De Clercq.e.. efavirenz. & Miroshnikova. the individual drugs may necessitate dose adjustments ther proceeded through preclinical and/or clinical so as to generate the optimal drug plasma levels. G. J... Balzarini... H.. M.. i.. 1840). tenofovir disoproxil L. the 2 . Other compounds have fur. M. & Egberink. emtricitabine and atazanavir.. Preliminary random. drug combina- New compounds have been licensed for clinical use: tions often lead to a synergistic action and diminish the virus entry inhibitor enfuvirtide (FuzeonTM ). Kukla. 46.1816 E. Y.. J. L. H. evaluation: CXCR4 antagonists (i. 17–20 September 2000..e. and two new P. et al. S. K. microbicides to prevent infection and transmission of the human pliance. A. K. HIV integrase inhibitors Andries. Antimicrobial Agents and least similar to that of conventional “highly active Chemotherapy. the the likelihood of resistance development. 2003). now several once-daily dose regimens have become & Iizawa. 2350–2355. 5698–5703. Yet other. A.. Acquired fumarate and lamivudine.P. Sawada. new anti-HIV agents My special thanks are due to Christiane Callebaut acting at new targets by novel mechanisms (which for her invaluable editorial assistance. A. E. Naesens. R. P.e. 25–30% (Louie et al.. (1999). M.3 -dideoxycytidinene. the once-daily dosing is likely to lectins from the Amaryllidaceae family qualify as efficient be accompanied by increased tolerability and com. Lewi. Kanzaki.. Nishimura. Preclinical studies on thiocarboxanilide UC-781 as a virucidal agent.. Okamoto. consisting of different drugs targeting different In recent years. et al. Van Damme. Laga. (2003). O. have been. Herdewijn. References glycopeptide antibiotics). on Antimicrobial Agents and Chemotherapy (no. Vermeire. integrase inhibitors such as S-1360..e.. Princen. In with a post-integration. M. Toronto. Conclusion multiple (for example. considerable progress has been viral proteins (or different sites of the same protein). (1986). However.. lopinavir/ritonavir.

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