MicrobiologyBytes: Virology: Antivirals Updated: April 8, 2009 Search

Antiviral Drugs

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Drug: Viruses: Chemical Type: Target:
Vidarabine Herpesviruses Nucleoside analogue Virus polymerase
Acyclovir Herpes simplex (HSV) Nucleoside analogue Virus polymerase
Gancyclovir and Valcyte ™ (valganciclovir) Cytomegalovirus (CMV) Nucleoside analogue Virus polymerase (needs virus UL98 kinase for activation)
Nucleoside-analog reverse transcriptase inhibitors (NRTI): AZT (Zidovudine), ddI (Didanosine), ddC (Zalcitabine), d4T (Stavudine), 3TC (Lamivudine) Retroviruses (HIV) Nucleoside analogue Reverse transcriptase
Non-nucleoside reverse transcriptase inhibitors (NNRTI): Nevirapine, Delavirdine Retroviruses (HIV) Nucleoside analogue Reverse transcriptase
Protease Inhibitors: Saquinavir, Ritonavir, Indinavir, Nelfinavir HIV Peptide analogue HIV protease
Ribavirin Broad spectrum: HCV, HSV, measles, mumps, Lassa fever Triazole carboxamide RNA mutagen
Amantadine / Rimantadine Influenza A strains Tricyclic amine Matrix protein / haemagglutinin
Relenza and Tamiflu Influenza strains A and B Neuraminic acid mimetic Neuraminidase Inhibitor
Pleconaril Picornaviruses Small cyclic Blocks attachment and uncoating
Interferons Hepatitis B and C Protein Cell defense proteins activated

Historically, the discovery of antiviral drugs has been largely fortuitous. Spurred on by success with antibiotics, drug companies launched huge blind-screening programmes - with relatively little success. Lead compounds were modified by chemists in an attempt to improve bioactivity. Solubility, stability, availability and activity are all important

Scientists would like to think rationale drug design could be accomplished i.e determine the structure of your target in a complex with a known inhibitor. Use this and other biochemical knowledge to "theoretically design" a better inhibitor. Make it and test it.

However in recent years combinatorial chemistry has become fashionable.This uses robotic techniques to make enormous numbers of different compounds from a limited number of subunits. The nature of the subunits can vary widely. Consider a library of 10 compounds. One reaction will give 100 different compounds.

1-1....1-10; 2-1...2-10; .....; 10-1....10-10. Two reactions will give 1000. Ten reactions will give one hundred thousand million!

The individual compounds, or pools of compunds are then assayed for bioactivity. Any active compounds identified can be used as a lead compound.

The key to success in drug development is specificity, e.g. Paul Erlich's "magic bullets". Any stage of virus replication can be a target for a drug, but drug must be more toxic to virus than to the host.

CHEMOTHERAPUTIC INDEX =

Dose of drug which inhibits virus replication / Dose of drug which is toxic to host

The smaller this value of this number the better, i.e. several orders of magnitude difference is required for a really safe drug.

Modern technology allows deliberate design of drugs, but to do this, need to "know your enemy":

Strategies for antiviral therapy

Commonly used therapuetically. ASAP after infection or clinical signs of infection. Prophylactic use occasionally. Any of the stages of viral replication can be a target for antiviral intervention. The only requirements are:
  1. That the process targeted be essential for virus replication.
  2. That the theraputic agent is active against the virus while having "acceptable toxicity" to the host organism

Attachment

This phase of replication can be inhibited in two ways:

a) Using agents which mimic the V.A.P. and bind to the cellular receptor, e.g:

b) Agents which mimic the receptor and bind to the V.A.P:

While the above are promising lines of experimental research, there are considerable problems with clinical use of any of these substances. The cost of synthetic peptides is prohibitive when the amounts required for clinically effective whole body doses; the generation of anti-idiotypic antibodies is a complex, poorly understood process; the pharmacokinetics of many of these synthetic compounds is very poor.

Penetration / Uncoating

It is difficult to specifically target these stages of the life cycle as relatively little is known about them. Uncoating in particular is largely mediated by cellular enzymes, although like penetration, is often influenced by one or more virus proteins.

Pleconaril is a broad spectrum anti-picorna virus agent. It is orally bioavailable and reduces peak viral titres by more than 99%; symptoms are improved. 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

Amantadine and rimantadine are active against influenza A viruses. The action of these closely related agents is complex and incompletely understood, but they are believed to block cellular membrane ion channels.

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 drugs currently in use.
The majority of these drugs function as polymerase substrate (i.e. nucleoside/nucleotide) analogues. The toxicity of these drugs varies considerably from some which are well tolerated (e.g. acyclovir) to others which are highly toxic (e.g. IdU/TFT/AZT). There is a serious problem with the pharmacokinetics of these nucleoside analogues, e.g. typically short serum half lives of 1-4h.

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

More recently, a series of other nucleoside analogues derived from these drugs and active against herpesviruses have been developed:

Nucleoside analogues active against HIV:

Gene Expression

Virus gene expression is less amenable to intervention than genome replication, since viruses are much more dependent on the cellular machinery for transcription, mRNA splicing, cytoplasmic export and translation than for replication.

Assembly / Maturation / Release

As stated above, for the majority of viruses, these processes are poorly understood. Two drugs with anti influenza activity are available, Relenza taken as an aerosol and Tamiflu taken as a pill. The latter is active against both A and B strains. Both function as neuraminidase inhibitors and prevent 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 minimised. Tamiflu is reported to be 90% effective as a prophylactic agent.


Other antiviral drugs:


Therapy of HIV Infection:

Several distinct classes of drugs are now used to treat HIV infection:
  1. Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). These drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and are incorporated into viral DNA (they are chain-terminating drugs).
  2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). In contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV replication directly by binding non-competitively to reverse transcriptase.
  3. Protease Inhibitors. These drugs are specific for the HIV-1 protease and competitively inhibit the enzyme, preventing the maturation of virions capable of infecting other cells.

Problems

Toxicity. AZT causes anaemia, in fact its toxicity is such that it was originally rejected as an anti-tumour drug! Interferon and acyclovir can cause severe nausia and vomiting. Pregnancy is an important contraindication because of possible teratogenic effects.

Detailed notes for these documents can be found in Chapter 6 of Principles of Molecular Virology.

CoverStandard Version: The 4th edition contains new material on virus structure, virus evolution, zoonoses, bushmeat, SARS and bioterrorism, CD-ROM with FLASH animations, virtual interactive tutorials and experiments, self-assessment questions, useful online resources, along with the glossary, classification of subcellular infectious agents and history of virology. (Amazon.co.uk)

Cover Instructors Version: The 4th edition contains new material on virus structure, virus evolution, zoonoses, bushmeat, SARS and bioterrorism, CD-ROM with all the Standard Version content plus all the figures from the book in electronic form and a PowerPoint slide set with complete lecture notes to aid in course preparation. (Amazon.co.uk)

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