Antiviral Drugs

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 =

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":

• Molecular biology - understanding viral replication and producing specific targets for inhibition
• Computer aided design (C.A.D.)

Strategies for antiviral therapy

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

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

• anti-receptor antibodies
• V.A.P. anti-idiotypic antibodies
• natural ligands of the receptor, e.g. epidermal growth factor/Vaccinia virus
• synthetic ligands, e.g. synthetic peptides resembling the receptor-binding domain of the V.A.P. itself.

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

• anti-V.A.P. antibodies (a natural component of the antibody response to virus infection/vaccination)
• receptor anti-idiotypic antibodies
• extraneous receptor, e.g. rsCD4/HIV
• synthetic receptor mimics, e.g. sialic acid derivatives/influenza virus.

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

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.

• The target for both drugs is the matrix protein (M2).
• Drug-treated cells are unable to lower the pH of the endosomal compartment (a function normally controlled by the M2 gene product), a process which is essential to induce conformational changes in the HA protein to permit membrane fusion.

Genome Replication

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

• Acyclovir is phosphorylated by HSV tk 200 times more efficiently than by cellular enzymes. The cell DNA polymerase is less sensitive to it than the viral DNA polymerase.
• Gancyclovir is 10 times more effective against CMV than acyclovir since it is specifically phosphorylated by a CMV-encoded kinase encoded by gene UL97 :

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

Assembly / Maturation / Release

Other antiviral drugs:

Therapy of 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).
   • Zidovudine (AZT = ZDV, Retrovir) first approved in 1987
   • Didanosine (ddI, Videx)
   • Zalcitabine (ddC, Hivid)
   • Stavudine (d4T, Zerit)
   • Lamivudine (3TC, Epivir)
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.
   • Nevirapine (Viramune)
   • Delavirdine (Rescriptor)
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.
   • Saquinavir (Invirase) first approved in 1995
   • Ritonavir (Norvir)
   • Indinavir (Crixivan)
   • Nelfinavir (Viracept)

Problems

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© MicrobiologyBytes 2007.