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Biochimica et Biophysica Acta 1587 (2002) 258 – 275

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Review
New developments in anti-HIV chemotherapy $
Erik De Clercq*
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received 24 January 2002; accepted 24 January 2002

Abstract

Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human
immunodeficiency virus (HIV) infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs): i.e. zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine
[( )FTC], tenofovir disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e. nevirapine, delavirdine,
efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to
the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for
chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates,
polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral
coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-779 derivatives); (iii) virus – cell fusion, through binding to the
viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2V-
dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-
dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol,
fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic
characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased
activity [‘‘second’’ or ‘‘third’’ generation NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are resistant to the ‘‘first’’
generation NNRTIs, or (iii) as in the case of PIs, a different, nonpeptidic scaffold [i.e. cyclic urea (mozenavir), 4-hydroxy-2-pyrone
(tipranavir)]. Nonpeptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Given the
multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating the mode of action of these
agents from cell-free enzymatic assays to intact cells. Two examples in point are L-chicoric acid and the nonapeptoid CGP64222, which were
initially described as an integrase inhibitor or Tat antagonist, respectively, but later shown to primarily act as virus adsorption/entry inhibitors,
the latter through blockade of CXCR4. D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Human immunodeficiency virus (HIV); Reverse transcriptase (HIV); Protease (HIV); CXCR4 (HIV); CCR5 (HIV); Integrase (HIV); Fusion (HIV);
Transcription (HIV)

Abbreviations: HIV, human immunodeficiency virus; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse
transcriptase inhibitors; PIs, protease inhibitors; DIBA, 2,2V-dithiobisbenzamide; ADA, azadicarbonamide; AIDS, acquired immune deficiency syndrome; HSV,
herpes simplex virus; STD, sexually transmitted disease; MIP-1a and -1h, macrophage inflammatory proteins; SDF-1, stromal-cell derived factor; PBMCs,
peripheral blood mononuclear cells; TM4, transmembrane segment; SI, syncytium-inducing; NSI, non-syncytium-inducing; NOBA, 3-nitrosobenzamide; AZT,
zidovudine; ddI, didanosine; ddC, zalcitabine; d4T, stavudine; 3TC, lamivudine; ABC, abacavir; bis(POM)-PMEA, bis(pivaloyloxymethyl)-9-(2-
phosphonylmethoxyethyl)adenine, adefovir dipivoxyl; bis(POC)-PMPA, bis(isopropyloxycarbonyloxymethyl)-(R)-9-(2-phosphonylmethoxypropyl)adenine,
tenofovir disoproxil; dOTC, (F)2V-deoxy-3V-oxa-4-thiocytidine; ( )FTC, emtricitabine; DAPD, amdoxovir, ( )-h-D-2,6-diaminopurine dioxolane;
bis(SATE)ddAMP, bis(S-acetyl-2-thioethyl)phosphotriester of ddA
$
Proceedings of the 8th International Symposium on Molecular Aspects of Chemotherapy, Gdansk, Poland, 5 – 9 September 2001.
*
Tel.: +32-16-337341; fax: +32-16-337340.
E-mail address: erik.declercq@rega.kuleuven.ac.be (E. De Clercq).

0925-4439/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 5 - 4 4 3 9 ( 0 2 ) 0 0 0 8 9 - 3

as chain termina. polyoxometalates. the sulfated polysaccharides extracted from sea algae [4]. polycarboxylates. whether synthetic or of natural origin. polysulfonates. before a more specific binding occurs . De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 259 1. A great variety of polyanionic compounds have been lamivudine (3TC). abacavir (ABC)]. Guidelines to the major clinical trials with these compounds are assumed to exert their anti-HIV activity by shielding off have been recently published [1]. patients with AIDS and AIDS-associated diseases.6]. E. delavirdine. All these compounds. as taining the polycarboxylate pharmacophore [3]. poly- (RT). Virtually all the last few years. zalcitabine (ddC). polyphosphates. non. ritonavir. lopinavir). etc. a the advent of so many new compounds other than those that primary binding site. polyphosphonates. nelfinavir. Virus adsorption (gp120) inhibitors steps (tenofovir) or three phosphorylation steps [zidovudine (AZT). at the substrate binding site of the reverse transcriptase virus adsorption (or binding) to the cell surface: i. comprising at least three anti. (ii) non-nucleoside reverse transcriptase inhibitors sulfates. virus attachment to the cell surface heparan sulfate. and that (iii) are targeted at well-defined steps available through expanded access programmes) for the in the HIV replicative cycle. has become will primarily address those new anti-HIV compounds that (i) the standard treatment of acquired immune deficiency have emerged as promising anti-HIV drug candidates during syndrome (AIDS) or HIV-infected patients. I human immunodeficiency virus (HIV) drugs. indinavir. described to block HIV replication through interference with tors. for the treatment of HIV infections. This class of substrate binding site (nevirapine. that. which is necessary for latently and chronically infected cells remains forbidding [2]. that (ii) are in preclinical or early-clinical drugs that have been licensed for clinical use (or made development. as well as peptidomimetics. following two phosphorylation 2. efavirenz). act. the virus-associated protease (saquinavir. compounds also comprises the cosalane analogues (1) con- and (iii) protease inhibitors (PIs) that specifically inhibit. (NNRTIs) that interact with the RT at an allosteric. treatment of HIV infections fall into one of the following three categories: (i) nucleoside/nucleotide reverse transcrip- tase inhibitors (NRTIs). will undoubtedly improve the prognosis of Combination therapy.e. Introduction have been formally approved. Here. didanosine (ddI). stavudine (d4T). amprenavir. the positively charged sites in the V3 loop of the viral Although the long-term goal of eradicating the virus from envelope glycoprotein (gp120) [5.

2. bicyclams had been known as potent and selective HIV phages (M-tropic or R5 strains). 3 and 7 of CCR5 [18].26]. as demonstrated. and Chlamydia trachomatis [11]. also inhibit other sexually transmitted ners [19] in the therapy and/or prophylaxis of HIV-1 disease (STD) pathogens. three compounds. before their not evolved simply to act as coreceptors for HIV entry. virus [8] and other flaviviruses (i. may nanomolar concentration range. it also explains why polysulfates have a broad. HSV. The clinical potential of TAK-779 and its conge- styrene)sulfonate). The normal ligands for CCR5 are RANTES replication of X4 HIV-1 strains within the nanomolar (‘‘regulated upon activation. The bicyclam AMD3100 (3) inhibits the cytokines). 4C [24] were announced as CXCR4 antagonists.000-fold higher concentrations [17]. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 to the CD4 receptor of the CD4+ cells.e. whereas for CXCR4. normal T-cell expressed and concentration range [28]. RANTES. namely SDF-1 (‘‘stromal-cell derived factor’’) has coreceptor of the CXCR4+ cells (the latter in the case of X4 been identified. but not M-tropic R5. Japanese encephalitis TAK-779. Neisseria gonorrheae infections remains to be further explored. TAK-779 does not induce internalization of stances. as it also being pursued as vaginal microbicides.e. i.Lys-7]polyphemu- sin or T22 [23] and the nonapeptide (D-Arg)9 or ALX40- To enter cells. further adds to their several new CCR5 antagonists have been reported potential therapeutic and preventive value. Almost simultaneously [22 – 24]. and cell-to-cell contact.e. Of these chemokines. CXCR4 is the coreceptor for bicyclams are the most specific and most potent CXCR4 HIV-1 strains that infect T-cells (T-tropic or X4 strains). Unlike addition to their anti-HIV activity. blocking the HIV-1 particles must interact. for example. again through the viral the replication of T-tropic X4. The fact that in demonstrates some antagonism towards CCR2b. only one natural or ratio of 50% cytotoxic concentration (CC50) to 50% . these polyanionic sub. Meanwhile. for poly(sodium(4. if applied as a vaginal formulation. first nonpeptidic molecule that has been described to block spectrum antiviral activity against HIV. as TAK-779 has been found to inhibit R5 HIV-1 strains in the these compounds. CXCR4 and CCR5 have inhibitors for a number of years [27. and to the CXCR4 ligand. As it is not toxic to the host secreted’’) and MIP-1a and -1h (‘‘macrophage inflamma. The CCR5 is the coreceptor for HIV-1 strains that infect macro.28]. The major role of polysulfates or polyanionic substances A binding site for TAK-779 has been identified within in general in the management of HIV infections may reside the transmembrane helices 1. tory proteins’’). The [12] or CCR5 coreceptor [13]. and a lead clinical candidate (SCH C) for further development has been identified. while not affecting X4 successfully block HIV infection through both virus-to-cell HIV-1 strains at 10. its selectivity index. CCR5. [Tyr-5. Heparan sulfate is MIP-1a has emerged as the most potent chemokine for widely expressed on animal cells and. cells at concentrations up to 500 AM. HSV and various the replication of M-tropic R5 HIV-1 strains at the CCR5 other enveloped viruses [10]. [20.15] as well as monocytes/macrophages viruses.260 E. in the prevention of sexual transmission of HIV infection. level [17]. with the CXCR4 coreceptor strains through selective antagonism of CXCR4. i.12. a quaternary ammonium derivative (2) is the virus) [9]. HIV-1 envelope glycoprotein gp120. they target of action was identified as the CXCR4 coreceptor normally act as receptors for chemokines (chemoattractant [22. as it is involved in inhibiting HIV-1 infection in peripheral blood mononuclear the virus-cell binding of a broad spectrum of enveloped cells (PBMCs) [14. following binding with the CD4 receptor. the LD78h isoform of and dual tropic X4/R5 HIV strains). and antagonists that have been described to date [25. These compounds therefore merit TAK-779 is not a ‘‘pure’’ CCR5 antagonist.29. dengue [16]. Viral coreceptor antagonists the bicyclam AMD3100 [22]. including herpes simplex virus (HSV) [7].30]. 3.21].

may not only duction (Ca2+ flux). including PBMCs. these strains switched from CXCR4 to CCR5 cor- eceptor use [33]. Following a phase I clinical trial A close correlation has been found. in achieving a marked reduction in viral load in the SCID-hu Thy/Liv mouse model [34]. aspartic acid) resi. effects of AMD3100 on the T-tropic HIV-1 NL4-3 strain such as breast cancer metastasis. the bicyclam AMD3100 [32]. The interaction of the X4 or R5 HIV-1 envelope gly- 1. and (iii) SDF-1-induced signal trans. concomi- tantly. AMD3100 has proved efficacious. These findings indicate that selective blockade of CXCR4 by AMD3100 may prevent the switch from the less pathogenic M-tropic R5 to the more patho- genic T-tropic X4 strains of HIV. When the bicyclam AMD3100 was added to PBMC infected with clinical HIV isolates displaying the syncy- tium-inducing (SI) phenotype. [36]. may represent crucial sites of interaction with at > 100. the aspartate gp120). In particular. AMD3100 range of 0. Viral fusion (gp41) inhibitors dues in the extracellular regions of CXCR4 must be involved in its interaction with both AMD3100 and SDF. which are all three coprotein gp120 with the coreceptor CXCR4 or CCR5. HIV-1 strains have proven sensitive to AMD3100 in PBMC. but not M-tropic. which then anchors through its amino terminus residues at positions 171 and 262. between the AMD3100 con. The inhibitory X4 HIV infections. suggesting an intimate relationship have great potential for the therapy and/or prophylaxis of between these three parameters [29. signaling through CXCR4 CXCR4. vice versa. Substitutions of a neutral amino acid residue respectively. is followed by a spring-loaded action of the for aspartic acid in the second extracellular loop generated viral glycoprotein gp41 (normally covered by the bulkier resistance to AMD3100 [31]. E. Negatively charged amino acid (i. recently entered phase II clinical trials in HIV-infected centrations required to inhibit (i) HIV-1 NL4-3 replication. over a concentration for safety in normal healthy volunteers [35]. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 261 antivirally effective concentration (EC50) can be estimated and TM6. alone and in combination with other anti-HIV drugs. located close to the (the ‘‘fusion peptides’’) into the target cell membrane. bicyclams. but also other pathologic processes. these strains reverted to the non-syncytium-inducing (NSI) phenotype. (ii) monoclonal antibody (mAb 12G5) binding to the Given their high potency and selectivity as CXCR4 CXCR4 coreceptor. and the V3 loop of X4 HIV gp120.e. which are at least partially have been demonstrated in a wide variety of cells expressing dependent of. individuals. This extracellular sides of the transmembrane segments TM4 initiates the fusion of the two lipid bilayers. tropic and dual-tropic. 4. that of the . such as AMD3100. antagonists. various T.1 – 1000 ng/ml. which in vivo heralds the progression to AIDS. and.30]. and. highly basic. or mediated by.000.

this I84S mutation did not occur in some of the tium formation) at concentrations ranging from 1 to 10 ng/ naturally RPR103611-resistant HIV-1 strains such as NDK. only nonpeptidic low-molecular-weight compound that has bic grooves on the surface of the N36 coiled coil in the been reported to block HIV-1 infection through interaction gp41 ectodomain become available for binding with ex. tants indicated that a single amino acid change. At the onset of the fusion process.e. T-20 achieved by (based on the mutations G237R and R252K emerging in the 15th day a 1. 104. Meanwhile.5. These data provide proof-of-concept that HIV linic acid derivative unrelated to RPR103611 or IC 9564. a betu- RNA [39]. An initial clinical trial has been carried out depend on the accessibility of gp41 [43]. previously called DP-178.262 E. 30 and 100 mg twice daily. fusion inhibitors are able to reduce virus replication in was reported to block the assembly and/or budding of HIV vivo. YK-FH312. that binds to the hydrophobic groove of N36 10 nM concentration range [41]. the hydropho. twice daily). agents 1249. was modeled elucidated. and for the with T-20 at four doses (3. ml. The exact mode of action of RPR 103611 remains to be cursor). membrane. in helical secondary structure: DP-178 consistently afforded HIV-1 gp41 is sufficient to confer drug resistance [42]. ference with a post-binding. HIV-1 gp120.to 105-fold lower than the cytotoxic concen. the action of RPR103611 has been thought to tration [38]. Sequence analysis of RPR103611-resistant mu- after a specific domain (within gp41) predictive of a. More recently.to 2. and phase I clinical trials have been initiated with T. with gp41: this triterpene derivative has been found to traneous inhibitors. Nucleocapsid protein (NCp7) Zn finger-targeted trials. intravenously. particles [45]. for zinc-ejecting compounds such as 3-nitrosobenzamide . whereby X = any amino acid] in the nucleocapsid T-20 when evaluated in vitro against HIV under the same (NCp7) protein [46] comprise the proposed molecular target conditions [40].0-fold reduction in plasma HIV gp120 of drug-resistant mutants) [44]. However. a 39-amino acid peptide derived from DP-107 (which is a 38-amino acid peptide corresponding to residues 558– The two zinc fingers [Cys-X 2 -Cys-X 4 -His-X 4 -Cys 595 of gp160). De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 viral envelope with that of the cellular plasma membrane The betulinic acid derivative RPR 103611 (5) is the [37]. I84S. such as DP-178 (T-20). has been proposed as the prime target the highest dose (100 mg. main of gp41 (or residues 643 – 678 in the gp160 pre. isomeric betulinic acid derivative IC 9564. T-20 has proceeded to phase II/III clinical 5. i. 10. 36-amino acid involved in the fusion of the virus with the cell plasma peptide corresponding to residues 127 –162 of the ectodo. T-1249 would be 10-fold more potent than (CCHC). apparently through inter- [37]. a 36-residue inhibit the infectivity of a number of HIV-1 strains in the peptide. 100% blockade of virus-mediated cell –cell fusion (syncy. envelope-dependent step T-20 (pentafuside) (4) is a synthetic. T-20. for 14 days) in 16 HIV-infected adults: at rather than gp41.

SRR-SB3 already equipped with a phosphonate group. its inhibitory effects on T-cell responses in vitro and in vivo [55] can hardly be attributed to an action targeted at the HIV NCp7 Zn fingers. the oral compounds should be able to interfere with both early prodrug forms [bis(pivaloyloxymethyl)-9-(2-phosphonylme- (uncoating. 3TC. In rhesus macaques infected with the highly pathogenic chimeric virus SHIV.2-dithiane-4. AZT. 2. From PMEA and PMPA.1-dioxide (di. and therefore (cyclic DIBA) [47]. Fozivudine tidoxil is a thioether lipid AZT conjugate that has recently passed phase II clinical trials [57] and should be as effective as. 6. thoxyethyl)adenine (bis(POM)-PMEA) or adefovir dipi- bly) of retrovirus replication.50]. d4T. at a time when disseminated infection and extensive viral replication had already been established and CD4 + T-cell loss had begun. for the treatment of hepatitis B virus (HBV) infections. Some preliminary evi- dence of efficacy was witnessed with add-on ADA in patients failing current antiretroviral therapy [54]. shown to dock nicely on the NCp7 Zn finger domains [53] and are believed to selectively target these Zn fingers without affecting the cellular Zn finger proteins. Electron microscopically. In contrast to the nucleoside analogues. The DIBAs are able to enter intact tenofovir disoproxil (8) fumarate. These active metabolite [58]. Their effect at the early phase voxyl (7). the nucleotide analogues PMEA and PMPA are .e. even after withdrawal of Although NOBA. ddI.2V-dithiobisbenzamide (DIBA). its action in vivo is likely to be multipronged. E. all these compounds must be phosphorylated to their 5V-triphosphate form. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 263 (NOBA). RT inhibitors targeted at the substrate binding site The substrate (dNTP) binding site of the HIV-1 RT is the target for a large variety of NRTI analogues. The former is in advanced phase III clinical trials with loss of infectivity and decreased proviral DNA syn. and bis(isopropyloxycarbonyloxymethyl)-(R)-9- (disassembly) may also be ascribed to cross-linkage among (2-phosphonylmethoxypropyl)adenine (bis(POC)-PMPA) or adjacent zinc fingers. Although ADA is an HIV NCp7 Zn-finger inhibitor. Of the NCp7-targeted compounds. thesis during acute infection [51]. dithiane and ADA have been tenofovir (after 12 weeks of treatment) [59]. DIBA. A new drug application be described as ‘‘core-freezing’’ [52]. and potentially better tolerated than. their selectivity indexes [ratio of CC50 (50% cytotoxic concen- tration) over EC50 (50% effective concentration)] are not that impressive [53]. (NDA) and market authorization application (MAA) has been recently filed for tenofovir disoproxil fumarate with the FDA (US) and EMEA (EU). led to prompt.5-diol. only need two phosphorylation steps to be converted to the thiane) [48] and azadicarbonamide (ADA) [49. AZT.1. ADA (6) has been the first to proceed to phase I/II clinical trials in advanced AIDS patients. disassembly) and late phases (packaging. respectively] have been virions and the cross-linkage of NCp7 in virions correlates prepared. certainly. ddC. whereas the latter has completed phase III clinical trials for the effect bestowed by DIBAs on virus morphology could the treatment of HIV infections. assem. As a rule. virtually complete suppres- sion of viral replication and long-term stabilization of CD4 + T-cell levels. 1. before they can act as competitive inhibitors/substrate analogues/chain ter- minators at the RT level. these studies should be further extended. respectively. which were sustained. tenofovir treatment initiated 1 week post-infection. and the yet experimental drug emtricitabine [( )FTC]. ABC. which have for several years [56] been recognized as efficacious drugs for the treatment of HIV infections: i. ADA may well interact with a variety of targets and.

3V-dideoxynucleotide (ddNMP) prodrugs cytes/macrophages [74].3V-dideoxynucleoside (ddN) ana. the methylenecyclopropane nucleoside analogues (and their phosphoro-L-alaninate diesters) [62. BCH- 10652 (dOTC) (11) has demonstrated activity against HIV-1 in the SCID-hu Thy/Liv model. Therefore. This ‘‘thymidine kinase bypass’’ explains the high logues to their active 5V-triphosphate form is the first anti-HIV activity of d4T aryloxyphosphoramidate deriva- phosphorylation step. Also in vitro. albeit at a relatively high dosage level (400 mg/kg/day) [67]. has proven active against AZT. Despite its struc- tural similarity to 3TC.e. This has been convincingly shown for the cyclo- [69]. aryloxyphosphoramidate derivatives of saligenyl derivative of d4TMP (14) in a number of cell d4T [i. it is considered for use in the multidrug combination therapy of HIV-1 and HBV infections. This approach has proven of ddA) can also be bypassed by using the cyclic sali- particularly successful for a number of NRTIs such as genyl approach [75.66]. . a d4T-MP prodrug containing at the lines [79]. not only under chemical-simulated hydrol- dAMP] (12) was synthesized and found to be 1000-fold ysis conditions but also under intracellular conditions more potent against HIV than the parent compound ddA [77. which is converted by adenosine deaminase to dioxolane guanine (DXG).264 E. ( )-h-D-2. Thus. [73]. and ddAMP. dOTC proved also active against 3TC-resistant HIV-1 (M184V).63] and the 4V-ethynyl nucleoside analogues [64] have recently been described as new anti-HIV agents. Cyclosaligenyl pronucleotides of 2V. The thymidine kinase (in the that. albeit reduced. Amdoxovir [DAPD.78]. once they have been taken up by the cells. So324. deliver case of d4T) and the adenosine deaminase (in the case the nucleotide (ddNMP) form.76]. the structurally related ( F )2V-deoxy-3V-oxa-4V-thiocytidine (BCH-10652.and 3TC-resistant HIV-1 strains and has proceeded to phase I/II clinical studies [65. After the d4T aryloxyphosphoramidate (13) has been taken up by the cells. d4T and ddA deliver exclusively the nucleotides d4TMP acetyl-2-thioethyl)phosphotriester of ddA [bis(SATE]d. d4TMP is released intracellularly The bottleneck in the metabolic pathway leading from and then processed onto its active metabolite d4TTP AZT and the other 2V. [( )FTC] (9) is in phase III trials for HIV and phase I/II trials for HBV.3V-dideoxyadenosine (ddA) and d4T. phosphate moiety a phenyl group and the methylester of alanine linked to the phosphate group through a phos- phoramidate linkage] have been constructed [70 – 72].dOTC) [60]. the bis(S. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 In addition to 3TC and ( )FTC.6-diaminopur- ine dioxolane] (10). Similarly. dOTC and its (+) and ( ) enantiomers still retained. activity against 3TC-resistant M184V and M184I HIV-1 mutants [68]. attempts have been made tives in thymidine kinase deficient cells and resting mono- at constructing 2V. the dioxolane purine nucleoside analogues [61].

The NNRTIs More than 30 structurally different classes of com. delavirdine and efavirenz) at the amino acid residues that surround the NNRTI-bind- have so far been formally licensed for clinical use in the ing site of HIV-1 RT. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 265 7. interact with a specific ‘‘pocket’’ site of the HIV-1 RT pounds have been identified as NNRTIs. emergence of NNRTI- . E. However. which is closely associated with. but distinct from. NNRTIs are notorious for targeted at a nonsubstrate binding site of the RT [80]. emivirine (MKC-442) (15) binding site is in advanced (phase III) clinical trials. that are specifically inhibitory to HIV-1 replication and the substrate binding site. RT inhibitors targeted at the allosteric. viz. nonsubstrate treatment of HIV-1 infections. rapidly eliciting resistance [82]. resulting from mutations Three NNRTIs (nevirapine. compounds [81]. and others are in preclinical or early clinical development.

000. capravirine) [88 – 90].94 – 96. the alkenyldiarylmethane combined with NRTIs and used from the beginning at (ADAM) series of compounds [98]. This compound was reported to inhibit quinazolinones DPC 961 and DPC 963.4-dihydro-2(1H)quinazolinones therapeutic index greater than 4. UC-781 has been recognized as a (retro)viru. the thiophene-ethylthiourea 2 replication (albeit at higher concentrations than those (TET) derivative HI-443 [95].5-dimethox- yphenylethyl]-NV-[2-(5-bromopyridyl]-thiourea (HI-236) [92].000. the imidazole derivative S-1153 (AG1549. ( )-6-chloro-2-[(1-furo[2.3-c]pyridin-5-yl-ethyl)thio]- 4-pyrimidinamine (PNU-142721) [91].4]thiadiazine derivative QM96521 [86]. the quinoxalinylethylpyridyl The thiocarboxanilide UC-781 (16) is an exceptionally thioureas (QXPTs) [100]. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 resistant HIV strains can be prevented if the NNRTIs are urea-PETT derivatives [97].e. the emivirine (MKC-442) deriv- potent inhibitor of HIV-1 replication [80]. and. R165335 (TMC125) an excellent candidate for further clinical development. It has been found ative SJ-3366 [101] and R165335(TMC125) [102]. possess cyclopropylalkynyl-4-trifluoromethyl-3. i.99. K103N. and to inhibit HIV- DPC 082 and DPC 083 [94]. DPC 083 (17) and R165335 (TMC125) (18) that showed mission of HIV from infected to noninfected individuals activity against L100I. HIV-1 replication at a concentration below 1 nM with a kenyl-4-trifluoromethyl-3. the 4-cyclopropylal. . [84]. This makes replens gel [85].4][1. exhibit higher potency than the ‘‘old’’ (‘‘first’’ generation) cidal agent. As a to restore the antiviral activity of AZT against AZT-resistant rule.4-dihydro-2(1H) remarkable features. UC-781 would seem an ideal candidate for application K103N + L100I and K103N + Y181C RT mutant strains in as a vaginal microbicide (virucide). the pyrido[1.2. the ‘‘new’’ (‘‘second’’ or ‘‘third’’ generation) NNRTIs HIV-1 [83]. Y181C. therefore. the cyclohexenylethylthiourea required for inhibition of HIV-1) at the viral entry stage derivatives HI-346 and HI-445 [96]. the pyrrolobenzoxaze- sufficiently high concentrations [80]. capable of reducing the infectivity of HIV-1 NNRTIs against wild-type and NNRTI-resistant HIV-1 virions. N-[2-(2.266 E.2a]indole derivative BCH-1 [93]. when formulated in the nanomolar concentration range [102]. the cis-cyclopropyl [101]. pinone (PBO) derivatives [99]. Y188L. such as SJ-3366 (19). To the new classes of NNRTIs that offer potent anti-HIV- 1 activity belong the thieno[3. the 4. This is particularly prominent for use in (retro)virucidal formulations to prevent the trans. Some of the new NNRTIs. the quinoxaline GW420867X [87].102]. yielding considerable promise for the [91.

12-trioxatricornan and hypericin [107] and a series of thiazolothiazepine derivatives. been described as inhibitors of HIV-1 integrase (for a DPC 963. and if they do exhibit anti-HIV activity. polyhydroxylated aromatic type of compounds. pur- purogallin. and 236 of the p66 RT subunit [89]. polyamides. DPC 082 and DPC 083 for clinical development recent review. Capravirine (AG1549) (20) has a favorable profile of resilience to many drug resistance mutations. Recently. this could. and host chromosome. have led to the selection attractive therapeutic target. like other derivatives [99] are orally bioavailable and penetrate well retroviruses. 4. HIV-negative individuals [103]. Numerous compounds have of PNU-142721 (21) for clinical studies [91].5-dicaf- . see Ref. which has been attributed to extensive main chain hydrogen bonding involv- ing the main chain of residues 101. integrase has been considered as an favorable pharmacokinetic profile. 3. including efavirenz. apparently due to a conformational change in the p66 subunit that resulted in enhanced binding to the p51 subunit. The problem with integrase inhib- itors is that while they might be effective in an enzyme- based assay. L-chicoric acid is structurally reminiscent of curcumin [112]. The broad. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 267 (+)-Calanolide A (22) is the only naturally occurring NNRTI: it was first isolated from a tropical tree (Calophyl- llum lanigerum) and has already been the subject of a phase I clinical study in healthy. Capravirine has proceeded to phase II/III clinical trials [90]. be attributed to antiviral actions targeted at other steps in the HIV repli- cative cycle. the retroviral enzyme integrase. including ellagic acid. at least in some cases. potent antiviral activity. [105]): for example. bisdistamycins and lexitropsins [106]. L-chicoric acid [109 – 111] is such a case. preferably pos- sessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups [108]. Since HIV. and DPC 961. were found to enhance the association between the RT subunits p66 and p51. E. an unexpected effect of NNRTIs on HIV-1 RT dimerization was documented [104]: several NNRTIs. cannot replicate without integration into a into the brain. It remains to be established if this enhanced dimerization has any bearing on the anti-HIV-1 potency of the NNRTIs. HIV integrase inhibitors Retrovirus integration requires at least two viral com- ponents. 103. and cis-acting sequences at the retroviral DNA termini U3 and U5 ends The NNRTIs cis-cyclopropylurea-PETT [97] and PBO of the long terminal repeats (LTRs). [94].8. their anti-HIV activity in cell culture may be masked by cytotoxicity. 8.

the structure of the HIV-1 integrase core compounds that specifically inhibit the transactivation of the domain complexed with an inhibitor [1-(5-chloroindol-3. This was followed by the number of receptors. such as the NF-nB inhibitors [120]. [116]. cells through interference with the transcription process: i. it was surmised that these diketo acids fluoroquinoline derivatives [122]. tives have been reported as inhibitors of HIV-1 integrase feoyltartaric acids (DCTAs) [115].4-dihydro-6-fluoro-1-methyl- dinucleotide (GT) from the 3Vend]. but also binds to a HIV-1 integrase inhibitors [117]. Furthermore. however. We have recently demon- strated [116]. mutations were found in the V2. V3 and V4 loop of gp120. HIV gene expression may be compounds known to interact at the virus adsorption level.4-dioxobutanoic acid deriva.e. Thus. Tat basic domain may provide great scope for therapeutic These compounds were also found to inhibit HIV-1 repli. additional 4-aryl-2. while no mutations were seen in the integrase. L-chicoric acid proved inactive against HIV strains that were resistant to polyanionic At the transcription level. however. inhibited by compounds that interact with cellular factors and time-of-addition experiments further corroborated an that bind to the LTR promoter and that are needed for basal interaction of L-chicoric acid at the virus adsorption stage level transcription. Starting from L-731. namely strand fluoro-1. Furthermore. rosmarinic acid [114] and dicaf. but integrase carrying the G140S mutation appeared to be as sensitive to the inhibitory effect of L-chicoric acid as the wild-type 9.4-dihydro-7-[4-(2-methoxyphe-nyl)-1-piperazinyl]- transfer [the other catalytic function being endonucleolytic 4-oxoquinoline-3-carboxylic acid] and (K-37) [7-(3. not only for translocation but also for nuclear strand transfer reaction that leads to the covalent linkage localisation and trans-activation. Upon repeated passages of the virus in the presence of the compound.e. 8-trifluoromethyl-4-oxoquinoline-3-carboxylic acid] (25) on 988 (24).988 muscle cells [121]: the basic domain of Tat may be and L-708. on smooth muscle and skeletal description of a number of diketo acids (such as L-731. Greater specificity. Transcription (transactivation) inhibitors integrase. Tat has pleiotropic effects: it not only acti- described as a platform for structure-based design of novel vates the transcription of HIV-1 RNA. have been reported to inhibit HIV-1 integrase. and thus targeting of the of the viral DNA 3Vends to the cellular (target) DNA [107]. intervention in HIV-1 infection [121]. The inhibitory effects of owe their antiviral activity exclusively to inhibition of one the fluoroquinolines (K-12) [8-difluoromethoxy-1-ethyl-6- of the two catalytic functions of integrase. mutations in the HIV-1 A number of compounds have been reported to inhibit integrase conferred resistance to the inhibitory effects of HIV-1 replication in both acutely and chronically infected the compounds on both strand transfer and HIV-1 infec.4-dehy- processing of the (pro)viral DNA to remove the terminal dro-4-phenyl-1-piperidinyl)-1. tivity [118]. Integrase was identified as the molecular target for the action of L-chicoric acid (23) since a single amino acid substitution (G140S) in the integrase rendered the corresponding HIV-1 mutant resistant to L-chicoric acid [111].268 E. and all these compounds [119]. cation in cell culture. the HIV-1 LTR-driven gene expression may at least in part . De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 feoylquinic acid [113]. HIV LTR promoter by the viral Tat (trans-activating) yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone] has been protein [120]. that L-chicoric acid owes its anti- HIV activity in cell-culture to an interaction with the viral envelope gp120. can be expected from those Recently.906) as inhibitors of the integrase-mediated important. i. We did confirm that in an enzymatic assay L- chicoric acid inhibited HIV integrase activity.

4-bis(3-(6-oxo. which is. replication in both acutely and chronically infected cells. We The bistriazoloacridone temacrazine [1. E. to block the Tat/TAR interaction. 2 and + 111 relative to the start of transcription [126]. on the other hand.1]acridin-5-yl-aminopropyl)piperazine] owes its anti-HIV activity in cell culture primarily to an (26) was found to block HIV-1 RNA transcription from the interaction with CXCR4. on the one hand. and. as expected. which is structurally reminiscent of the amino acid 48 – 56 sequence RKKRRQRRR of Tat. CXCR4 . polypeptidic. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 269 be attributed to inhibition of Tat [123] or other RNA. encompassing the Tat core domain (amino acid residues 36 –50) [127]. Tat peptide analogs. the coreceptor for X4 HIV strains HIV proviral DNA without interfering with the transcription [130]. these peptide analogs were able to effectively block the Tat transactivation process. that the peptoid CGP64222 6H-v-triazolo[4. and. The 9-mer peptoid CGP64222 (27).5. have demonstrated. Resistance was generated upon serial passage of the virus in the presence of temacrazine and was associated with several unique nucleotide changes in HIV-1 LTR at positions 1. was also reported. or the basic domain (amino acids 48 – 56: RKKRRQRRR) [128] have been reported to inhibit HIV-1 replication. not surprising given the structural of any cellular genes [125]: the compound inhibited HIV-1 similarity of CGP64222 to the other. perhaps. to suppress HIV-1 replication [129]. however. dependent transactivators [124].

Tat itself (following its extracellular release) has recently been shown to block CXCR4-depend. P-TEFb is a protein kinase composed of viz. nelfinavir. which has been accredited with a favorable resistance profile that does not parallel any of the other PIs currently in clinical use. This has prompted the search for new. an and the nascent transcript from the HIV-1 LTR promoter. The reason for this combination is that ritonavir strongly inhibits the metabolism of lopinavir and allows lopinavir to reach much higher plasma drug levels upon oral administration [135]. All six licensed PIs follow the same principle. and. H. 10. might also offer increased oral bioavailability and/or pharmacokinetic properties. Tat forms a triple navir. thus arresting maturation and thereby block- Flavopiridol (L86-8275. Examples of nonpeptidic PIs of HIV protease include 4-hydroxycoumarins and 4- . share the same structural determinant. ative properties. flavopiridol (28) which makes them nonscissile substrate analogues for the was found to block Tat transactivation. i.e. indinavir. peptidomimetric inhibitors of HIV protease. Lopinavir is co-dosed with ritonavir at 400/100 mg twice daily. nonpeptidic inhibitors of HIV protease. which is in clinical have been tailored after the target peptidic linkage in the gag trials for the treatment of cancer because of its antiprolifer. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 antagonists such as T22 [23] and nona-arginine (ALX40. In fact. they act as peptidomimetic inhibitors of HIV protease [134]. concomitantly. ritonavir.270 E. All PIs that are currently transcription by RNA polymerase II (through phosphoryla. namely saqui- tion of the carboxyl-terminal domain). that is. p6. which. Resistance mutations have been reported for most. p24. HIV PIs 4C) [24]. The HIV PIs ent kinase (Cdk) and P-TEFb inhibitor. as well as a favorable pharmacokinetic profile that would allow once-daily dosing [136]. the phenylalanine – proline sequence at positions 167 Cdk9 and cyclin T1 and secures the elongation phase of and 168 of the gag-pol polyprotein. HMR1275) is a cyclin-depend. p2. hydroxyethylene (instead of the normal peptidic) bond. HIV protease. amprenavir and lopi- complex with P-TEFb (composed of Cdk9 and cyclin T1) navir. presumably through blockade of precursor polyproteins to the structural proteins (p17. In phase III clinical trials is atazanavir (BMS-232632) (29). Consistent with its ability to block P-TEFb. also inhibited HIV replication [132]. ing infectivity of the nascent virions [133]. if not all. CXCR4 by the above-mentioned 48– 56 amino acid portion p7. and gag-pol polyproteins that are cleaved by the protease. RT/RNase (RKKRRQRRR) of the molecule. integrase). licensed for the treatment of HIV infection. in addition to a broader anti-HIV activity spectrum. HIV PIs prevent the cleavage of the gag and gag-pol ent HIV-1 infection [131]. p1) and functional proteins (protease.

and number of compounds are capable of interacting with more proteasome inhibitors. shown to inhibit gag polyprotein processing as well as tives [138]. offer Independently of the HIV protease itself. they show no any step of the virus replicative cycle: adsorption. Conclusions appears to have good antiviral activity and tolerability at all doses tested [146]. Two examples in point are the DCTA L- . with multidrug resistance to other PIs [147]. cyclic cyanoguanidines [141].e. entry. have been than one target. In addition to the that were resistant to the established (peptidomimetic) ‘‘newer’’ NRTIs. furthermore. aza-dipeptide ana. tran- Tipranavir (31) showed low cross-resistance to HIV strains scription (transactivation) and maturation. reverse transcription. including man [140]. and tipranavir (PNU-140690). CXCR4 marked activity against HIV-1 isolates derived from patients and CCR5 antagonists) and virus-cell adsorption/fusion (i. While a potentially [139. In recent years. NNRTIs and PIs.6-dihydro-4-hydroxy-2-pyrone [143 – 145].140]. interesting approach. integration. specificity in their anti-HIV action so as to suppress virus The major advantage of the cyclic urea mozenavir (DMP. a sulfonamide.e. Quite a play a role in the processing of the gag polyprotein. sulfonamide-substituted deriva. The new aza-dipeptide analogues com. replication without (overt) cytotoxicity. fusion. such as epoxomicin. De Clercq / Biochimica et Biophysica Acta 1587 (2002) 258–275 271 hydroxy-2-pyrones [137]. E. DMP-323 and DMP-450) HIV maturation and release [148]. i. those that are targeted at viral entry (i. various other com- inhibitors of HIV protease [145]. cyclic ureas (i. compounds interacting with either gp120 or gp41). 450) (30) is its substantial oral bioavailability observed in all species examined. an ever increasing number of compounds bine excellent anti-HIV potency with high blood drug levels have been uncovered as anti-HIV agents targeted at virtually after oral administration. it remains to be seen whether inhib- logues [142]. and.e. DMP-450 has been the subject of phase I/II dose-escalating clinical studies and 11. proteasomes great potential for the treatment of HIV infections. itors of the proteasome/ubiquitin system display sufficient containing 5. Also. tipranavir retained pounds.e. uncoating. cross-resistance with saquinavir-resistant HIV strains [142].

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