Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Social history of viruses wikipedia , lookup
Bacteriophage wikipedia , lookup
Viral phylodynamics wikipedia , lookup
History of virology wikipedia , lookup
Virus quantification wikipedia , lookup
Introduction to viruses wikipedia , lookup
Endogenous retrovirus wikipedia , lookup
Oncolytic virus wikipedia , lookup
Antiviral Drugs 1 • Limited selective toxicity – Viruses mostly use host cell machinery, so very few unique targets – Most drugs block steps that take place within cells, increasing chances for cell toxicity. • Virucidal vs. virustatic – Can you kill something most people don’t say is alive? Viruses and biological principles • Drugs are specific against specific viruses – Further restricts number of effective drugs – Unlike bacteria, e.g. where all have 70S ribosomes • Viruses have uncertain evolutionary origin – Appear to have evolved independently • E.g. influenza (RNA) vs. Herpes – Competitive exclusionary principle • Viruses can’t occupy same niche • Even related Herpes viruses are different 2 3 Animal Virus Life Cycle http://192.207.64.1/field_research/M2.htm1.gif Steps in viral life cycle available as drug targets 4 • Viral attachment to cells/penetration – Highly specific interaction, 1st step in infection – Ex: Enfuvirtide, anti-HIV drug • Blocks folding of gp41 protein, prevents fusion of virus with host cell membrane. • Uncoating of virus – For most viruses, nucleic acid must leave the capsid for transcription or replication. – Ex: Amantadine, anti-flu drug Steps in viral life cycle available as drug targets-2 5 • Viral DNA/RNA synthesis – Enzymes needed for replication of viral nucleic acid are either unique targets (reverse transcriptase) or more sensitive than host enzymes to drugs. – Numerous examples: many are nucleoside analogs that are phosphorylated, inhibit enzymes. • Viral protein synthesis – Listed in table, but?? Nothing that might not be better grouped elsewhere – Can’t inhibit ribosomes w/o killing host cells Steps in viral life cycle available as drug targets-3 6 • Inhibition of specific enzymes – Overlap: many enzymes that viruses bring are for nucleic acid synthesis, e.g. reverse transcriptase (rt) or RNA-dependent RNA synthetase. – Didoxy nucleosides important as rt inhibitors, azido group in place of 3’ OH . – HIV protease inhibitors: assembly step? Steps in viral life cycle available as drug targets-4 • Inhibit viral assembly – Proteins attach to nucleic acid, to membrane – Many viruses bud, taking host membrane w/ viral proteins embedded. – HIV makes long precursor protein which is then cut into functional proteins by HIV protease • Protease inhibitors such as saquinavir, ritonavir, and indinavir block this step. 7 Block viral release • Oseltamavir and zanamivir: • Influenza has H and N spikes – H for attachment to surface glycoproteins. – N is neuraminidase which must remove terminal sialic acid residues from glycoproteins or new virions will attach on way out, get stuck. –Drugs inhibit neuraminidase; don’t stop viral replication, but prevent viral spread. 8 Steps in viral life cycle available as drug targets-4 • Stimulate/assist immune system – Natural human peptides used as drugs – Interferon • Inhibit protein synthesis • Degrade viral RNA – immunoglobulin 9 Pharmacokinetics 10 • Many available orally – Acid stability and good absorption – Necessary for long term HIV treatment • Some so toxic that only topical rx possible • Compartment trapping: acyclovir – Anti-Herpes guanosine analog – Enter cells, phosphorylated by viral thymidine kinase; further phosphorylated to triphosphate – Trapped in cell, accumulates to high effective dose Toxicity • More than with antibiotics, related to primary mode of attack on virus – Numerous drugs inhibit nucleic acid polymerases, producing side effects in actively multiplying cells • Much like effect of ionizing radiation, causing bone marrow damage, loss of blood cells. • Some toxicity unrelated: Foscarnet – Chelates divalent cations – Causes hypolcalcemia and hypomagnesemia • Results in seizures and cardiac dysrhymias 11 HIV 12 • More drugs vs. HIV than any other virus – Seriousness of illness, availability of unique targets – Reverse Transcriptase • Nucleoside analogs act as competitive inhibitors and dideoxys prevent chain elongation • Non-nucleosides bind at other site, inhibit – Protease inhibitors prevent protein processing – Fusion inhibitors (subcut inj only) – Always given in combination