|MicrobiologyBytes: Virology: Antivirals||Updated: April 8, 2009||Search|
|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.
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":
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.
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.
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:
Detailed notes for these documents can be found in Chapter 6 of Principles of Molecular Virology.
Standard 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)
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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