Antiviral Drugs
| 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":
- Molecular biology - understanding viral replication and producing
specific targets for inhibition
- Computer aided design (C.A.D.)
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:
- That the process targeted be essential for virus replication.
- That the theraputic agent is active against the virus while having
"acceptable toxicity" to the host organism
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