Antiviral Drugs

By
Rushikesh Diware
Asst. Professor
RSCP Buldhana
Introduction
• Viruses are microscopic infectious agents that require host cells to replicate.

• They can cause a wide range of diseases, from the common cold to severe respiratory
illnesses and deadly pandemics.

• Viruses exhibit rapid mutation rates, leading to the emergence of drug-resistant strains.

• They are acellular, that is, they contain no cytoplasm or cellular organelles.

• They carry out no metabolism on their own and must replicate using the host cell's
metabolic machinery. In other words, viruses don't grow and divide. ...

• The vast majority of viruses possess either DNA or RNA but not both.
Introduction
• Viruses are not proper living things

• consists of a genome;

• they are smaller in size with simple chemical composition,

• Can store few enzymes stored in a capsule made up of protein and rarely covered with a lipid layer.

• The viruses only replicate within the host cell and the viral replication depends primarily on the metabolic

processes of the invaded cell.

• Viruses does not possess cell wall, but they have RNA or DNA enclosed in a shell of protein known as capsid.

• The capsid is composed of several subunits known as capsomers.

• In certain cases, capsid may be surrounded by an outer protein or lipoprotein envelope

Introduction
• Smallest of all self-replicating organisms,

• Able to pass through filters that retain the smallest bacteria

• The simplest viruses contain a small amount of DNA or RNA surrounded by an uncomplicated protein coat.

• Some of the more complex viruses have a lipid bilayer membrane surrounding the nucleic acid.

• Viruses must replicate in living cells,

• The most basic requirement is for the virus to induce either profound or subtle changes in the host cell

• Viral genes are replicated and viral proteins are expressed.

• This will result in the formation of new viruses, usually

• Many more than the number that infected the cell initially.

• Viruses conduct no metabolic processes on their own

• depend totally on a host cell which they invade

• Utilize the subcellular machinery.

• They use part of the cell’s equipment for replication of viral nucleic acids

• expression of genes

• all of the cell’s protein synthesis machinery, and all of the cell’s energy stores that are generated by
its own metabolic processes.

• Turns the biochemical systems of the host cell to its own purposes,

• Completely subverting the infected cell.

• An infection that result in the production of more viruses than initiation of infection is called a
productive infection.

• The actual number of infectious viruses produced in an infected cell is termed the burst size.
Introduction
• One group of RNA virus that deserves special mention are reteroviruses.

• They are responsible for acquired immuno defi ciency syndrome (AIDS) and T-leukaemias.

• Reteroviruses contain reverse transcriptase (RT) enzyme

• That makes a DNA copy of the viral RNA template.

• Then, the DNA copy is integrated into the host genome

• at which it is referred to as provirus and is transcribed into both the genomic RNA and
mRNA for translocation into the viral proteins,

• giving generation to new virus particle

• They not only take nutrition from the host cell but also direct its metabolic
machinery to synthesize new virus particles.
• Viral chemotherapy, drugs have been developed which target virus
specific steps like
• cell penetration,
• uncoating,
• reverse transcription,
• virus assembly or maturation
• release from host cell, etc. Another stumbling block is that
Introduction

• https://youtu.be/jkNxmTrrZSk?si=Zc8WwrRKInGnIjUA

• https://youtu.be/QHHrph7zDLw?si=VZApv7vBdQsu8U-B

• https://youtu.be/Rpj0emEGShQ?si=sjyV9-AT32pBrQ0g
CLASSIFICATION OF VIRUSES
Viruses are classified on the basis of several features:
• Nucleic acid content (DNA or RNA)
• Viral morphology (helical, icosahedral)
• Site of replication in cell (cytoplasm or nucleus)
• Coating (enveloped or nonenveloped)
• Serological typing (antigenic signatures)
• Cell types infected (B lymphocytes, T lymphocytes,
monocytes)
Classification of antiretroviral Drugs

• I. Chemoprophylaxis
• A. anti -influenza: Amantadine, Rimantadine

• B. Neuraminidase Inhibitors: Zanamivir And Oseltamivir

• C. Interferons: Interferon Alfa (Intron A, Roferon A) And Interferon Beta (Betaseron)

• II. Nucleoside Antimetabolites: Inhibiting Viral Replication

• A. Inhibitors of DNA Polymerase: Idoxuridine, Cytarabine, Trifluridine, Vidarabine,
Adefovir Dipivoxil, Acyclovir, Valacyclovir, Ganciclovir, Famciclovir and
Penciclovir, Cidofovir, Foscarnet Sodium
• B. Reverse Transcriptase Inhibitors: Zidovudine, Didanosine, Zalcitabine,
Stavudine, Tenofovir disoproxil, Lamivudine, Emtricitabine,

• C. Miscellaneous Nucleoside Antimetabolites: Ribavirin

• III. Newer Agents For The Treatment Of HIV Infection

• A. Nonnucleoside Reverse Transcriptase Inhibitors: Nevirapine,

Delavirdine, Efavirenz,

• B. HIV Protease Inhibitors: Saquinavir, Indinavir, Ritonavir, Amprenavir,

and Nelfinavir, Lopinavir, Atazanavir, Fosamprenavir, Tipranavir,
TARGETS FOR THE PREVENTION OF
VIRAL
INFECTIONS—CHEMOPROPHYLAXIS
• Immunization
• Artificially acquired active immunity

• Safe and highly effective vaccines are available

• polio, rubella, measles, mumps, influenza, yellow fever, encephalitis, rabies,

smallpox, hepatitis B.
• vaccine must be sufficiently antigenic

• Capable to induce an effective antibody response

• must not cause the disease or some other toxic manifestation

Biochemical Targets for Antiviral Therapy

• Antiviral Drug development is more complex than antibacterial

• Virus require host cell for culture and incubation

• Complicated for drug screening in viral as compare to bacterial drugs

• They use host biochemical mechanism

• fewer specialized targets for potential attack

• successes of immunization procedures prevent lack of interest in
antiviral chemotherapy

• symptoms do not appear until the infection is well established

• for many common viral infections, chemotherapy is simply not an

appropriate choice of treatment
• Chemotherapeutic agents are needed to combat viruses that cause
severe or chronic infections, such as encephalitis, AIDS, and herpes
Chemoprophylaxis Influenza
• Amantadine and Rimantadine
• Interfere with penetration of host cells by viruses
• block earlystage replication.
• Amantadine, 1-adamantanamine hydrochloride
• its -methyl derivative rimantadine, α-methyl-1-adamantane
methylamine hydrochloride
• used for years as a treatment for Parkinson disease
• inhibit replication of the influenza type A viruses
• Rimantadine is generally 4 to 10 times more active
• they inhibit an early step in viral replication
• most likely viral uncoating
• in some strains, they affect viral assembly, possibly by interfering
with hemagglutinin processing
• Target of action is the influenza type A virus M2 protein
• no effect on influenza type B
• ADR: central nervous system and are dopaminergic.
• excreted
• largely unchanged in the urine.
NEURAMINIDASE INHIBITORS: ZANAMIVIR AND
OSELTAMIVIR

• Two macromolecules, surface glycoproteins, are embedded in the lipid

envelope: hemagglutinin and neuraminidase.

• Hemagglutinin is important for binding of the virus to the host cell

membrane by a terminal sialic acid

• Neuraminidase is an enzyme.

• It functions in several of the early activation steps of the virus

• occurs in both influenza A and B viruses.

• Neuraminidase is believed to be a sialidase,

• cleaving a bond between a terminal sialic acid unit and a sugar.

• This action is important in enhancing the penetration of viruses into host cells,

• enhances the infectivity of the virus

• If the sialic acid–sugar bond is prevented from being cleaved,

• the viruses tend to aggregate

• the migration of viruses into host cells is inhibited

• Neuraminidase inhibitors are clinically useful agents in blocking

• the spread of the viruses

ADR
• Zanamivir :lung disease (chronic obstructive lung disease or asthma)
to have shortness of breath, trouble breathing, or wheezing

• Oseltamivir: nausea, vomiting, diarrhea, bronchitis, abdominal pain,

dizziness, headache, cough, insomnia, vertigo, and fatigue
NUCLEOSIDE ANTIMETABOLITES: INHIBITING VIRAL REPLICATION

• Inhibitors of DNA Polymerase

• Idoxuridine: 5-iodo-2-deoxyuridine
• introduced in 1963 for the treatment of herpes simplex keratitis.

• The drug is an iodinated analog of thymidine

• Inhibits replication of several DNA viruses in vitro

• enters the cell and is phosphorylated at O-5 by a viral thymidylate kinase to yield a
monophosphate, which undergoes further biotransformation to a triphosphate

• Act as both a substrate and an inhibitor of viral DNA polymerase

• causing inhibition of viral DNA synthesis

• altered DNA due to iodine leads to faulty transcription

• Approved only for the topical treatment of herpes simplex virus (HSV) keratitis

• Solution of idoxuridine in dimethyl sulfoxide is available for the treatment of

herpes labialis, genitalis, and zoster

• Drug lacks selectivity

• Inhibit the growth of uninfected host cells

• ADR: redness. Itching. Swelling of the eye. Increased sensitivity to light and
glare

• Low virus selectivity, higher local toxicity and rapid development of viral
resistance, use of idoxuridine is restricted to superficial dendritic keratitis
Trifluridine

• It is a fluorinated nucleoside which acts in the same way as idoxuridine,

• Inhibits hsv-1, hsv-2, cmv and related viruses.

• However, virus selectivity is low and dna synthesis in host cells is also
affected due to blockade of cellular kinases.

• Trifluridine eye drop is approved for use in h. Simplex keratitis.

• Higher efficacy than idoxuridine eye drops is reported.

• Ocular irritation and lid edema can occur.

Acyclovir

• Acyclovir is active only against herpes group of viruses

• requires a virus specific enzyme for conversion to the active metabolite

• inhibits DNA synthesis and viral replication

• 20% of an oral dose of acyclovir is absorbed

• Used in Genital Herpes simplex, Mucocutaneous H. simplex, H. simplex encephalitis, H. simplex

(type I) keratitis, Herpes zoster, Chickenpox

• ADR: opical: Stinging and burning sensation after each application.

• Oral: The drug is well tolerated; headache, nausea, malaise and some CNS effects are reported.
Ganciclovir
• 9-[(1,3-dihydroxy-2-propoxy) methyl]guanine) DHPG (Cytovene),

• an analog of acyclovir

• Additional hydroxymethyl group on the acyclic side chain.

• This structural modification, while maintaining the activity

• against HSV (Herpes simplex virus) and VZV (Varicella-Zoster virus)

possessed by acyclovir,

• Greatly enhances the activity against CMV (Cytomegalovirus) infection

• Phosphorylated inside the cell

• Selectively inhibits viral DNA polymerase

• Incorporated into viral DNA causing strand breakage and cessation of elongation.

• Limited by the toxicity

• Causes myelosuppression, producing neutropenia, thrombocytopenia, and

anemia.

• These effects are probably associated with inhibition of host cell dna polymerase

• Potential central nervous system side effects include headaches, behavioral

changes, and convulsions.

• Mutagenic, carcinogenic, and teratogenic in animals.

Valacyclovir
• valyl ester Prodrug
• improved oral bioavailability (55–70%)
• due to active transport by peptide transporters in the intestine.
• it is completely converted to acyclovir in the first passage by
esterases.
• >3 fold higher plasma levels of acyclovir are obtained
• it is the drug of choice in herpes zoster.
• It is excreted in urine as acyclovir with a t½ of 3 hours.
Reverse Transcriptase Inhibitors
• An early event in the replication of HIV-1 is reverse transcription

• whereby genomic RNA from the virus is converted into a cDNA–RNA complex,

• then into double-stranded DNA ready for integration into the host chromosome.

• The enzyme that catalyzes this set of reactions is reverse transcriptase.

• RT actually operates twice prior to the integration step.

• Its first function is the creation of the cDNA–RNA complex

• In the second step, the RNA chain is digested away by RNase H, whereas RT creates the
double-stranded unintegrated DNA
• All of the agents are 2,3- dideoxynucleoside analogs.

• These compounds share a common mechanism of action in inhibiting the RT of

HIV.

• RT acts early in the viral infection sequence,

• Inhibitors of the enzyme block acute infection of cells

• Even though the RT inhibitors share a common mechanism of action,

• their pharmacological and toxicological profiles differ dramatically.

1. https://youtu.be/SURGNo44wmU?si=Sk_-KqgXacjxOUXL

2. https://youtu.be/cC9kyoAo1ac?si=0tFji18KzEJEhNlC

3. https://youtu.be/G9FeQKcxVZY?si=SGyLbVHL2OS7GZIp
Zidovudine
• 3-azido-3-deoxythymidine or AZT

• analog of thymidine that possesses antiviral activity

• Active against HIV-1, HIV-2, HTLV-1, and several other retroviruses.

• This nucleoside was synthesized in 1978 by Lin and Prusoff

• active against retroviruses

• AIDS and some kinds of leukemia.

• Zidovudine triphosphate competitively inhibits RT

• symptomatic HIV infection (AIDS or ARC)

• ADR: hematological toxicity, Anemia and granulocytopenia, Anaemia and neutropenia

• Retroviruses possess a RT or an RNA-directed DNA polymerase

• The drug enters the host cells by diffusion

• phosphorylated by cellular thymidine kinase

• converts the monophosphate into diphosphates and triphosphates

• Zidovudine triphosphate competitively inhibits RT

• The 3-azido group prevents formation of a 5,3-phosphodiester bond

• causes DNA chain termination, yielding an incomplete proviral DNA

• Zidovudine monophosphate also competitively inhibits cellular thymidylate

kinase
Didanosine
• 2’,3’-dideoxyinosine
• synthetic purine nucleoside analog that is bioactivated to 2’,3’-dideoxy-
ATP
• inhibits RT and is incorporated into viral DNA to cause chain termination
in HIV infected cells.
• potency of didanosine is 10- to 100-fold less than that of AZT
• less myelosuppression than AZT causes
• Used in advanced HIV infection
• ADR: Painful peripheral neuropathy, pancreatitis
Zalcitabine,

• 2,3-dideoxycytidine or ddCyd,
• is an analog of cytosine
• activity against HIV-1 and HIV-2,
• including strains resistant to AZT.
• more active in populations of monocytes and macrophages as well as in
resting cells.
• inhibits host mitochondrial DNA synthesis
• bioavailability 80%
• ADR: peripheral neuropathy, characterized by pain, paresthesias, and
hypesthesia, beginning in the distal lower extremities, fatal pancreatitis
Stavudine
• 2, 3-didehydro-2-deoxythymidine (D4T,
• causes termination of viral DNA elongation through its incorporation
into DNA.
• short half-life (1–2 hours)
• excreted largely unchanged (85%–90%)
• ADR: peripheral neuropathy.
Lamivudine
• (-)-2,3-dideoxy-3-thiacytidine, (-)-β-L- (2R,5S)-1,3-oxathiolanylcytosine, 3TC, or
(-)-(S)-ddC.
• unnatural stereoisomer (-)-(S)- ddC exhibits greater antiviral activity against
HIV than the natural enantiomer (+)-(S)-ddC
• Synthetic nucleoside analog
• differs from 2,3-dideoxycytidine (ddC) by the substitution of a sulfur atom in
place of a methylene group at the 3-position of the ribose ring.
• Exhibited highly promising antiretroviral activity against HIV and low toxicity in
the dosages studied.
• Resistance to lamivudine develops rapidly
• lamivudine caused substantial increases in CD4+ counts
Tenofovir Disoproxil
• prodrug analogously with abacavir.
• monophosphate nucleotide related to AMP, which is active against HBV as well
as HIV.
• low oral absorption, it is used as the disoproxil ester prodrug, which not only
improves bioavailability, but also intracellular passage of the active form.
• hydrolysis of the prodrug is dephosphorylated by cellular kinases into
tenofovir diphosphate
• which preferentially inhibits HBV-DNA polymerase and HIV-reverse
transcriptase
• Affinity for host DNA-polymerase is very low.
• It also gets incorporated in the viral DNA to cause chain termination
• Plasma and tissue esterases cleave the phosphate protecting groups, releasing
the active drug.
Nonnucleoside Reverse Transcriptase Inhibitors

• Do not require bioactivation by kinases to yield phosphate esters

• Not incorporated into the growing DNA chain

• Bind to an allosteric site that is distinct from the substrate (nucleoside triphosphate)-
binding site of RT

• Can combine with either free or substrate-bound enzyme

• Nnrtis exhibit a classical noncompetitive inhibition

• Extremely potent

• Do not inhibit mammalian DNA polymerases

• chief problem with the NNRTIs is the rapid emergence of resistance

• Occur due to point mutations in the gene coding for the enzyme

• Crossresistance between NNRTIs is more common

• use combinations with the nucleosides to reduce toxicity

• nevirapine (Viramune), the delavirdine (Rescriptor), and efavirenz

have been approved for use in combination with NRTIs

• treatment of HIV infection.

 Nevirapine
• more than 90% absorbed by the oral route

• widely distributed throughout the body.

• It distributes well into breast milk and crosses the placenta.

• Transplacental concentrations are about 50% those of serum.

• drug is extensively transformed by cytochrome P450 (CYP) to inactive

hydroxylated metabolites;

• undergo enterohepatic recycling. t1/2 45 to 23 hours,

ADR: liver problems and severe skin rash and allergic reactions.
Delavirdine
• must be used with at least two additional antiretroviral agents to treat
HIV-1 infections.
• The oral absorption of delavirdine is rapid, and peak plasma
concentrations develop in 1 hour.
• Extensive metabolism occurs in the liver by CYP isozyme 3A (CYP3A)
• Bioavailability is 85%. 98% protein bound. The half-life is 2 to 11 hours,
elimination is 44% in feces, 51% in urine, and less than 5% unchanged in
urine.
• induces its own metabolism.
• ADR: rash along with other symptoms such as fever, blistering, sores in
the mouth, red or swollen eyes, or muscle or joint pain. hives.
Efavirenz
• mandated for use with at least two other antiretroviral agents.
• morethan 99% protein bound, and high CSF concentrations.
• Metabolism occurs in the liver.
• The half-life 52 to 76 hours,
• (the drug induces its own metabolism).
• Peak concentration is achieved in 3 to 8 hours.
• Elimination is 14% to 34% in urine (as metabolites) and 16% to 41% in feces
(primarily as efavirenz). The oral dosage form is supplied as a capsule.
• headache,
• rashes, dizziness, insomnia and neuropsychiatric symptoms, Gynaecomastia
HIV Protease Inhibitors

• is an enzyme that cleaves gag-pro propeptides to yield active enzymes

• that function in the maturation and propagation of new virus.

• The catalytically active protease is a symmetric dimer of two identical 99 amino acid
subunits

• each contributing the triad Asp-Thr-Gly to the active site

• designed to mimic the transition state of hydrolysis at the active site;

• HIV PIs are designed to mimic the transition state of hydrolysis called as analog
inhibitors
• HIV PIs are aimed at arresting replication of the virus at the maturation
step to prevent the spread of cellular infection,

• they should possess good oral bioavailability

• relatively long duration of action to vaoid Resistance develops by point

mutations

• high–molecular-weight, dipeptide- or tripeptide-like structures low

water solubility.
• E. g. Atazanavir (ATV), Indinavir (IDV), Nelfinavir (NFV), Saquinavir
(SQV), Ritonavir (RTV), Lopinavir (in combination with ritonavir LPV/r),
Fosamprenavir (FPV) and Darunavir (DRV)
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•
• https://youtu.be/MK2r8J7SCSg?si=ku8llQnBv9qAX68X
Saquinavir (Invirase)89
• is well tolerated following oral administration.

• Absorption of saquinavir is poor but is increased with a fatty meal. not

distribute into the CSF,

• and it is approximately 98% bound to plasma proteins.

• extensively metabolized by the firstpass effect.

• Bioavailability is 4% from a hard capsule and 12% to 15% from a soft capsule.
• Saquinavir lowers p24 antigen levels in HIV-infected patients, elevates CD4+
counts, and exerts a synergistic antiviral effect when combined with RT inhibitors
such as AZT and ddC

• should be used in combination with at least two other antiretroviral drugs to

minimize resistance.

• ADR: pain or tenderness in the upper stomach, pale stools, dark urine, loss of
appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin.
 Indinavir
• When administered with a high-fat diet,

• achieves a maximum serum concentration of 77% of the administered dose.

• The drug is 60% bound in the plasma.

• It is extensively metabolized by CYP3A4, and seven metabolites have been identified.

• Oral bioavailability is good, with a tmax of 0.8 0.3 hour. T

• he half-life is 1.8 hour

• Indinavir also causes dyslipidemia.

• The available dosage forms are capsules of 200 mg, 333 mg, and 400 mg.

• ADR: Gastrointestinal: Nausea, diarrhea, abdominal pain, and dry mouth

• Skin: Dry skin and lips, jaundice, and hives

Ritonavir
• an antiretroviral medication used along with other medications to treat HIV/AIDS
• This combination treatment is known as highly active antiretroviral therapy
(HAART).
• Ritonavir is a protease inhibitor, though it now mainly serves to boost the
potency of other protease inhibitors
• It may also be used in combination with other medications to treat hepatitis C
and COVID-19
• It is taken by mouth. Tablets of ritonavir are not bioequivalent to capsules, as
the tablets may result in higher peak plasma concentrations.
• ADR: nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands
and fee
Synthesis of acyclovir