Antiviral agents
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Antiviral Agents . Introduction. Because viruses are obligate intracellular parasites, identification of safe and effective antiviral therapies is difficult. The best antiviral drugs inhibit a specific step in viral replication or pathogenesis.

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Antiviral Agents

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Antiviral Agents


Introduction

  • Because viruses are obligate intracellular parasites, identification of safe and effective antiviral therapies is difficult.

  • The best antiviral drugs inhibit a specific step in viral replication or pathogenesis.

  • Drug discovery can be accomplished by screening or rational design.

  • The emergence of virus mutants resistant to antiviral drugs is a serious problem.

  • Combination of targeted delivery strategies to control toxicities and resistance.


Drug Discovery/Development Pipeline

Today's Focus

  • Multifaceted, complicated, lengthy process

Clinical Pharmacology

& Safety

Pre-clinical Pharmacology

Pre-clinical Safety

Products

Discovery

Exploratory Development

Full Development

Phase I

Phase II

Phase III

0

15

5

10

12 -15 Years

Drug

Idea


The pathway for drug discovery


Drug Development

  • Viruses are now becoming better understood and several viral genomes have been properly mapped.

  • Scientists are now looking for the best drug targets

  • The main point of interest is any viral protein that the host organism does not normally produce

  • Once these viral proteins are identified they are tested using a large scale screening process to test for effectiveness


Drug Development

  • Antiviral candidates are tested in mass quantities

  • Antiviral drugs generally have strange side effects and a high toxicity

  • As with any pathogenic agent, Viruses evolve and develop resistance.

  • Thus the need for new drugs always exists


Drug Development

There are several known methods that the makers of Antiviral drugs are looking at, including:

  • Prevention of Viral Entry

  • Targeting the RNA/DNA replication in the cell

  • Targeting the transcriptase factors for Viral DNA

  • Destroying Viral proteases so that viral proteins are not cut and rearranged in optimal order

  • Stopping the release of the mature viruses from the host cell


  • The development of antiviral agents lagged significantly behind the development of antibacterial drugs.

  • Early drugs were highly toxic.

  • Analysis of the steps of viral replication has identified potential targets for antiviral drugs (e.g. structures, enzymes or processes).

  • Inhibitors of Attachment include anti-receptor antibody, natural ligands and synthetic ligands.


  • Inhibitors of Penetration and uncoating

  • Amantadine and Rimantadine:-

  • They are hydrophobic amines (weak organic bases) with clinical efficacy against influenza A only.

  • They concentrate in and buffer the contents of the endosomal vesicles preventing uncoating.

  • Their specificity stems from their ability to bind to and block the proton channel formed by the M2 matrix protein.


Influenza Treatment with Ion Channel Blockers Amantadine & Rimantadine

  • Prevent seasonal influenza A in 70-80% of cases

  • Can reduce severity & duration of illness if started within 48 hrs of onset of symptoms.

  • Treated persons may shed resistant virus after 5-7 days of treatment (sometimes as early as 2-3 days). All pandemic H1N1 strains are resistant.

  • Treatment should be discontinued after 3-5 days of treatment or within 24-48 hrs after disappearance of signs/symptoms).


  • Pleconaril

  • It is a broad spectrum antipicorna virus agent.

  • It is a small cyclic drug which binds to a canyon pore of the virus.

  • In doing so it blocks attachment and uncoating of the viral particle.

  • It is orally bioavailable and can reduce peak viral titers by more than 99%.


  • Inhibitors of Genome Replication

  • Many viruses have evolved their own specific enzymatic mechanisms to preferentially replicate virus nucleic acids at the expense of cellular molecules.

  • There is often sufficient specificity in virus polymerases to provide a target for a specific antiviral agent and this method has produced the majority of the specific antiviral agents currently in use.


  • The majority of these drugs function as polymerase substrate, i.e. nucleoside analogues.

  • Toxicity varies considerably.

  • There is a serious problem with the pharmacokinetics of these nucleoside analogues (typically short serum half lives of 1-4 hours).

  • Nucleoside analogues are in fact pro-drugs, since they need to be phosphorylated before becoming effective. This is the key to their selectivity.


Nucleoside Analogues

Acyclovir (acycloguanosine )- ACV.

  • Close to a perfect antiviral drug (specific, nontoxic).

  • Highly effective against herpes simplex virus (HSV), less so against varicella -zoster virus (VZV).

  • Highly selective and extremely safe.

  • Acyclic guanine derivative (differs from guanosine by having an acyclic side chain) that inhibits viral DNA synthesis.


Antiviral DrugsNucleoside and Nucleotide Analogs

Figure 20.16a


  • It is a prodrug, a precursor of the antiviral compound.

  • Activation of the drug requires three kinase activities to be present in the cell to convert acyclovir to a triphosphate derivative, the actual antiviral drug.

  • It is phosphorylated by a virus thymidine kinase (200 times more efficiently than by cellular enzymes) producing a monophosphate form.

  • Cellular enzymes complete phosphorylation to the di - and triphosphate forms.


  • The triphosphorylated form competes with GTP inhibiting the enzyme (DNA polymerase) and causing termination of the growing viral DNA chain because of lack of 3' OH group.

  • ACV affinity to viral polymerase is more than 100 folds that to cellular polymerase.

  • Acyclovir has no effect on host DNA replication because the first kinase activity is not found in an noninfected cell.


Antiviral DrugsNucleoside and Nucleotide Analogs


  • Valacyclovir

  • the valyl ester derivative of ACV is more efficiently absorbed and rapidly converted to ACV increasing its bioavailability.

  • Penciclovir and famciclovir are related drugs.

  • Ganciclovir

  • It differs from ACV by the addition of a single hydroxymethyl group in the acyclic side chain; the result is a remarkable activity against CMV.

  • It is phosphorylated by a virus-encoded kinase (not thymidine kinase).


  • Adenine arabinoside (vidarabine)- Ara -A

  • A purine analogue (identical to adenosine but arabinose is substituted for ribose).

  • Phosphorylated by cellular enzymes ( toxicity?) to inhibit both viral and cellular polymerases but viral is 6-12 times more sensitive.

  • It was used for HSV and VZV before ACV.


Azidothymidine (Zidovudine) AZT

  • Dideoxy analog of thymidine

    (a synthetic thymidine analogue) that Inhibits viral DNA synthesis by inhibiting the reverse transcriptase enzyme.

  • It has higher affinity to RT (100 times) than to cellular DNA polymerase.


  • Efficiently phosphorylated (several steps of phosphorylation) to triphosphate by cellular kinases

  • AZT monophosphate competes with thymidine monophosphate

  • Much less selective than acylovir and has side effects

  • Does not eliminate previously incorporated provirus


  • Dideoxyinosine (Didanosine, ddI)

  • Dideoxycytidine (Zalcitabine, ddc)

  • Stavudine (d4t)

  • Lamivudine (3Tc).

  • All are inhibitors of reverse transcriptase used for the treatment of HIV infection.

  • Ribavarin

  • An analogue of guanosine but the base ring is incomplete and open.

  • It is active against DNA and RNA viruses by inhibiting inosinemonophosphatedehydrogenase and the synthesis of the mRNA 5- cap and RNA polymerase.


  • Iododeoxyuridine (Idoxyuridine)

  • Trifluorothymidine (Trifluridine)

  • Fluorouracil

  • All are analogues of thymidine and they inhibit the biosynthesis of thymidine or replace it and become incorporated in DNA.

  • Nucleotide Analogue (cidofovir)

  • It has the phosphate group attached and it inhibits DNA polymerase .


  • Nonnucleoside polymerase Inhibitors

  • Foscarnet: anti-herpes viruses.

  • Nevirapineanddelaviridine : anti HIV

  • Protease Inhibitors

  • Anti HIV: Saquinavir, Indinavir, andRitonavir

  • Anti HCV: Boceprevir and Telaprevir

  • The Unique structure of HIV protease and its essential role in the production of a functional virion has made this enzyme a good target for antiviral drugs.


  • Uncleavable mimics of gag- pol polyprotein

  • Inhibits HIV protease

  • Does not eliminate previously incorporated provirus but does prevent further spread

  • Resistance due to protease alterations


  • Inhibitors of Assembly, Maturation and Release

  • Zanamivir/ Relenza (aerosol)

  • Oseltamivir / Tamiflu (tables)

  • Peramivir/ IV for emergency use in hospitalized adults or children

  • Active against influenza as they are inhibitors of neuraminidase preventing the release of budded viruses from the cell.

  • Because they act late in the life cycle of the virus it is hoped that problems with resistance emergence will be minimized.


Neuraminidase Inhibitors Zanamivir & Oseltamivir

  • Mechanism: blocking of the active site of neuraminidase; prevents removal of sialic acid residues and results in clumping of viral progeny

  • Effective against influenza A & B.

  • Effective when flu symptoms are < 2 days old.

  • Inhibitors reduce disease syndrome by 1 day.

  • May decrease influenza secondary complications

  • Antiviral resistance can occur, but much less frequently than with the ion channel blockers amantadine or rimantadine


  • Neuraminidase inhibitors appear to have similar efficacy to the amantidine & rimantidine ion channel blockers for prevention & treatment of influenza

  • Neuraminidase inhibitors have Less Central Nerveous System side effects, but more Gastro-Intestinal effects

  • Neuraminidase Inhibitors are more expensive, but there is less risk of inducing virus resistance.


  • Methisazone

  • It is of historical importance as an inhibitor of poxviruses.

  • It was highly virus specific and did not affect cellular metabolism.

  • It blocked a late stage in viral replication resulting in the formation of immature, noninfectious virus particles.


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