1 Antiviral Drugs 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?

2 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

3 Animal Virus Life Cycle

4 Steps in viral life cycle available as drug targets Viral attachment to cells/penetration –Highly specific interaction, 1 st 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

5 Steps in viral life cycle available as drug targets-2 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

6 Steps in viral life cycle available as drug targets-3 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?

7 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.

8 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.

9 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

10 Pharmacokinetics 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

11 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

12 HIV 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