Antivirals

DR.RAHUL

Antiviral Agents

04/11/2023DR RAHUL KUNKULOL

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VIRUSES Viruses are made up of core genome

of nucleic acid contained in a protein shell called Capsid

Surrounded by lipoprotein membrane called envelope (Genome + Capsid + Envelope = Virion)

Viruses are obligate intracellular parasite ie. do not have a metabolic machinery of their own – uses host enzymes

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VIRUSES• Certain viruses multiply in the

cytoplasm but others do in the nucleus

• Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly.

• Most multiplication take place before diagnosis is made


Types of Viruses• DNA viruses• Adenoviruses (upper respiratory infections)• Herpes simplex (genital herpes)• Hepadna virus (hepatitis B)• Cytomegalovirus (CMV)• Varicella (chickenpox) and varicella-zoster• Smallpox

• RNA viruses : Influenza A and B

• RNA retroviruses : Human immunodeficiency virus (HIV)


Viral Replication

Adsorption to and penetration of susceptible cells.

Synthesis of early, nonstructural proteins.

Synthesis of RNA or DNA.

Synthesis of late, structural proteins

Assembly of viral particles and release


DNA Viral replication cycle

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RNA Viral replication cycle

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Targets for Antivirals


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Viral uncoating

Nucleoside analogs

Non-nucleoside polymerase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Protease inhibitors

Neuraminidase inhibitors

Anti-Viral drugsMany antiviral drugs are Purine or Pyrimidine analogs.Many antiviral drugs are Prodrugs. They must be phosphorylated by viral or cellular enzymes in order to become active.Anti-viral agents inhibits active replication The viral growth resumes after drug removal.


Anti-viral drugsCurrent anti-viral agents do not eliminate non-replicating or latent virus

Effective host immune response remains essential for the recovery from the viral infection

Clinical efficacy depends on achieving inhibitory conc. at the site of infection within the infected cells


ClassificationAll are DNA polymerase inhibitors

Nucleoside Analogues:(Herpes, CMV, HIV, R.Syncitial)

Purine analoguesAcyclovir ValacyclovirGanciclovir ValganciclovirPenciclovir FamciclovirCidofovir (c) Adefovir (a)

Vidarabine (a) Pyrimidine analogues

IdoxuridineTrifluridine


Classification Non Nucleoside:(Herpes )

Foscarnet (Direct inhibitor of DNA polymerase and RT)

mRNA synthesis inhibitorRibavirin Fomivirsen

Inhibitors of viral uncoating: (Influenza)

Amantadine Rimantadine Neuraminidase inhibitor

Zanamavir Oseltamivir Non selective antivirals

Interferon-alpha (Hepat. B&C, Herpes)04/11/2023DR RAHUL KUNKULOL 12

Antiviral DrugsNucleoside and Nucleotide

Analogs

Figure 20.16a04/11/2023DR RAHUL KUNKULOL 13

Acyclovir & Congeners :

• Valacyclovir is a prodrug of Acyclovir with better bioavailability.

• Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability.

• Penciclovir is used only topically whereas Famciclovir can be administered orally.

• All are guanine nucleoside analogs.


Acyclovir: Mechanism of Action


Nucleoside AnaloguesGeneral Mechanism of Action

1. Taken up by cells

2. Converted by viral and cellualr enzymes to the triphosphate form

3. The triphosphate form inhibits:• DNA polymerase

• Reverse transcriptase

• RNA polymerase

4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.


Acyclovir Valacyclovir (prodrug, better availability)

A Guanine analogue with antiviral for Herpes group only

Acyclovir AcycloGMP AcycloGTP

Thymidine kinase Cellular kinases

Viral 200x affinityof mammalian

1. Inhibits viral DNA polymerase selectively2. Incorporated into DNA and terminates synthesis


Active against HSV-1 (Labial

and ocular infection)

HSV-2 (Genital infection)

Varicella-zoster infections

Epstein barr virus

Resistance :HSV and varicella zosterDeficiency in

thymidine kinase activity

Changes in virus directed enzymes

Acyclovir (ACV)


THERAPEUTIC USES


Genital Herpes (HSV-II)

• Primary disease : • Acyclovir 5% ointment 6 times a

day for 10 days• Late & severe cases: 400 mg TDS

orally for 10 days • Recurrent disease:• Iv infusion 5mg/kg over 1 hr

repeated 8 hrly for 10 days• Followed by suppressive

treatment with oral acyclovir


HSV-I


• Mucocutaneous :• Remains localized to lips and

gums (Acyclovir skin cream)• H.Simplex encephalitis • 10 mg /kg /8hr iv acyclovir for 10

days• H. Simplex keratitis (HSV–I)• Acyclovir eye ointment 5 times a

day for 3days

Other uses…….


Chickenpox : Oral 400mg TDS for 7 days

Herpes zoster infections Acyclovir less active

Adverse effects• Oral : • Headach, N/v, diarrhea, vertigo

• IV : • Phlebitis, rash , hypotention• Nephrotoxicity

• Reversible neurological manifestations


Ganciclovir

• Mechanism like Acyclovir • Active against all Herpes viruses

including CMV• Low oral bioavailability given I.V.• Drug of choice for CMV

infections: retinitis, pneumonia, colitis…


Adverse effects

Bone marrow suppression (leukopenia 40%,

thrombocytopenia 20%) CNS effects

(headache, behavioral, psychosis, coma, convulsions) 1/3 of patients have to stop because

of adverse effects


Guanine

Acyclovir Ganciclovir


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Cidofovir Approved for the treatment of CMV retinitis in immunocompromised patients Nucleoside analog of cytosine Gets converted to only cidofovir

diphosphate and inhibit viral DNA polymerase

It inhibits viral DNA synthesisAvailable for IV, Intravitreal inj, TopicalNephrotoxicity is a major disadvantage.Uses : CMV retinitis


AdefovirAdenosine analogue

Converted by cellular kinases to active diphosphate

Inhibits Hepatitis B virus DNA polymerase

Gets incorporated into DNA causes Chain termination

Use: Chronic hepatitis B

AE : Nephrotoxicity, lactic acidosis, hepatomegaly.


Vidarabine Adenine nucleoside analogue Convert to Ara-A triphosphate and

inhibit DNA polymerase Active against HSV and vaccina virus

› Treatment of HSV encephalitis and herpetic keratitis

Poor solubility, given i.v. with big volume of fluids (2.5 L) ⇒ risk of fluid overload


ADVERSE EFFECTS

GI Bone marrow Hypokalemia Inappropriate ADH secretion; Psychosis; painful neuropathy; Not a drug of choice for anything :

Replaced by Acyclovir because of toxicity and problems in administration.


Idoxuridine（ IDU）

• Active against HSV and VZV• First pyrimidine analogue used as

antiviral.• It is iodinated derivative of

deoxyuridine.• MOA same as acyclovir


Uses• Topical use for treatment of HSV

infections of the eyelid, cornea and skin.• Only indication-

Herpes simplex kerato-conjunctivitis• High toxicity :• Bone marrow depression

• Due to incorporation of idoxuridine into host cell DNA


Direct inhibitor of DNA polymerase and RT :

Foscarnet

• An inorganic pyrophosphate analog

• Active against Herpes (I, II), Varicella , CMV, including those resistant to Acyclovir and Ganciclovir.

• Direct inhibition of DNA polymerase and RT

• Very poor oral bioavalibility so given slow iv.


Uses

• CMV retinitis and other CMV infections instead of Ganciclovir.

• H simplex resistant to Acyclovir

• H. simplex in AIDS patients


Adverse effects• Nephrotoxicity (25%) most

common ADR• Hypocalcaemia (chelates divalent

cations)• Others: Hypokalemia,

Hypomagnesaemia


Ribavirin

Inhibit replication of both DNA and RNA viruses

Triphosphate inhibits RNA polymerase

Anemia due to hemolysis and BM suppression


Uses

Ribavirin is the drug of choice for:• RSV bronchiolitis and pneumonia in

hospitalized children (given by aerosol)

Ribavirin is an alternative drug for:• Influenza, Parainfluenza, Measles

virus infection in immunocompromised patients


Fomivirsen• Is a Oligonucleotide

• Primarily an anti CMV agent

• Binds to mRNA and inhibit synthesis of immediate early proteins needed for replication

• Injected intravitreally for : CMV retinitis in patients of AIDS

• A/E: Iritis, Vitreitis.


Antiviral Therapies for Influenza


Viral uncoating inhibitors

Amantadine Rimantadine

• Chemically a tricyclic amine not related to any nucleotide

• Inhibit penetration of virus to cells ,the uncoating of certain virus and viral replication.

• M2 protein which acts as ion channell appears to be its one of the target.

• Prevent diseases caused by influenza A

• Treatment of Parkinson’s disease


Adverse effects• GI upset• Headache• Nervousness• Postural hypotension, ankle edema


• Inhibit neuraminidase enzyme of influenza• Enzyme essential for release of virus

• Examples: zanamivir and oseltamivir• Zanamivir administered via inhalation• Oseltamivir administered orally• Oseltamivir is converted to O.

carboxylate (oral bioavalibility 80%)

Neuraminidase inhibitor


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Uses and Adverse effects

• Therapeutic Use• Treatment of acute uncomplicated

Influenza A (H1N1 virus, swine flu) : Oseltamivir 75mg BD

• Prevention : 75mg OD

• Adverse effects• N/V, Bronchospasm and

abnormal respiratory function


Interferons

• Three classes of interferons – α , β, γ • α and β interferons: produced by all

the cells in response to viral infections• γ interferon : produced only by T

lymphocyte and NK cells in response to cytokines – immune regulating effects

• γ has less anti-viral activity compared to α and β interferon


Mechanism of action

Induction of the following enzymes:A protein kinase which inhibits protein synthesisAn oligo-adenylate synthase which leads to degradation of viral mRNAA phosphodiesterase which inhibit t-RNA

The action of these enzymes leads to an inhibition of translation


Interferons

• Interferon prevent spread of viruses to new cells (Viral hepatitis)

• Natural products of the immune system in viral infections

• Antiviral, anticancer and immuno-modulating

• Toxicity: flu-like syndrome, BM suppression; CNS

• Use :Hepatitis B and C04/11/2023DR RAHUL KUNKULOL 48

Antivirals Spectrum

Acyclovir HSV-1, HSV-2, VZV, Shingles.

Ganciclovir CMV

Famciclovir Herpes genitalis, shingles

Cidofovir CMV

Adefovir HBV

Idoxuridine, Trifluridine

Herpetic keratoconjunctivitis


Antivirals Spectrum

Foscarnet HSV, CMV in AIDS

Ribavirin RSV, Parainfluenza

Fomivirsen CMV retinitis in AIDS

Amantidine, Rimantidine

Influenza A Virus

Oseltamivir H1N1 influenza

Interferon HBV, HCV04/11/2023DR RAHUL KUNKULOL 50

Virus

DiseasesDrug(s) of choice

Alternative drugs

Inf. A

Influenza

Amantadine Rimantadine

RSVPneumonia,bronchiolitis

Ribavirin(aerosol)

HSV

Genital herpes

Acyclovir

Foscarnet

Keratitis

Conjunctivitis

TrifluridineIdoxuridineVidarabine

Encephalitis

Acyclovir

Neonatal HSV

infection

Acyclovir

Vidarabine

Herpes infections in

immunocompromised host

Acyclovir

Foscarnet


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In normal host

No therapy

Immunocompromised host, or pregnancy

Acyclovir

Foscarnet

CMV

Retinitis

Ganciclovir

Foscarnet

HCV

InterferonsHepatitis B

Hepatitis C

VZV

CMV


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HBV

Recent...... ENTECAVIR:• Guanosine analogue

• Competitively inhibits viral DNA polymerase

• Approved by FDA in march 2005 for treatment of chronic hepatitis B

• Oral bioavailibility : 95%

• AE : Headach, fatigue, NV


Recent...... Peramivir• Neuramidase inhibitor

• Approved in 2009

• For emergency treatment of hospitalised patients of H1N1 infection

• Used iv for patients resistant to Oseltamivir, zanamivir….


Health & Medicine

Antivirals