Lecture 20 - HSV and HIV Antiviral Drugs Flashcards
Path of antiviral drug discovery 1) 2) 3) 4) 5) 6)
1) A medical need is identified
2) Relevant mechanism is found through research
3) High-throughput screens of libraries of natural or drug-like products.
4) Successful candidates put through mechanism-based screens.
5) Lead compound selected
6) Drug candidate selected, goes into clinical testing
Drugs that block virus attachment
1)
2)
1) Maraviroc, HIV attachment/entry inhibitor
2) T20 (fuzeon), HIV fusion inhibitor
Drugs that block uncoating
Amantadine, blocks influenza A M2 ion channel
Drugs that block genome synthesis
1)
2)
1) Acyclovir, polymerase inhibitor of herpesviruses
2) Zidovudine, HIV RT inhibitor (NRTI and NNRTI)
Drugs that interfere with RNA synthesis
Ribavirin - Nucleoside analogue
Interferon
Drugs that interfere with protein synthesis
1)
2)
1) Interferons
2) Saquinivir, Darunavir - HIV protease inhibitors
Drugs that interfere with viral release
1) Zanamivir (Relenza)
2) Ostelamivir (Tamiflu) - Both inhibit action of neuraminidase in influenza.
Effect of pegylation
Improves bioavailability
Effects of IFN-induced proteins
Depending on virus or cell type, these proteins inhibit viral penetration or uncoating, synthesis of mRNA, translation of viral proteins and/or viral assembly or release
How are IFN therapies administered?
Injection of purified recombinant proteins
What does Amantadine do?
Binds the two diagonally-located alpha-helices of the M2 ion channel in the influenza envelope.
Prevents acidification, fusion of viral envelope with endosome.
How is Zanamivir administered?
Inhaled powder
How does Zanamivir interfere with influenza NA?
Sialic acid mimetic. Replaces OH group of sialic acid with guanidine, which forms two bonds with the floor of NA binding pocket.
How does Ostelamivir interfere with influenza NA?
Sialic acid mimetic. Replaces glycerol with a hydrophobic group, which binds strongly to the wall of the NA binding pocket.
Maraviroc
CCR5 coreceptor antagonist. Blocks HIV attachment/entry.
HIV viruses that Maraviroc works on
C5 viruses. Doesn’t work against X4 viruses.
What do fusion inhibitors act on in HIV?
Prevent gp41 conformational change.
CXCR4 coreceptor antagonist
AMD11070 (used to treat X4 HIV)
Nucleoside
A nucleotide without any phosphate groups
Where on a nucleotide are the phosphate groups?
5’ position of sugar group
Substrate for DNA polymerisation
Nucleoside triphosphate
Acyclovir
A guanosine analogue.
Has no phosphate groups, lacks 3’ OH required for extension of DNA polymer.
Requires HSV thymidine kinase to attach a phosphate to 5’.
Derivatives of acyclovir that have improved bioavailability
Prodrugs. EG: Valacyclovir has a valine attached to 5’ OH group, which is cleaved off within a cell.
The valine assists in the drug passing across the wall of the intestinal tract.
Ribavirin 1) 2) 3) 4) 5)
1) A guanosine analogue
2) Inhibit the replication of many DNA and RNA viruses in vitro
3) Shaped like a guanine, but nitrogen base is incomplete.
4) Has 2’, 3’ and 5’ OH group on ribose sugar. Therefore affects RNA polymerisation, not DNA.
5) Unphosphorylated. 5’ phosphorylation occurs within cell.
Which form of ribavirin affects viral RNA formation?
Tri-phosphorylated form
Ribavirin uses
1)
2)
3)
1) Aerosolised, IV - RSV, influenza
2) Oral or IV - Lassa, ebola
3) Oral - Hepatitis C, in combination with IFN
HIV reverse transcriptase inhibitor mechanism
1)
2)
3)
1) Thymidine analogues
2) Phosphorylated by cellular kinase to a tri-phosphorylated form
3) Used by viral RT in preference to normal thymidine, prevents chain elongation
Example of a HIV RT inhibitor
Zidovudine (AZT)
How does zidovudine differ from thymidine?
3’ OH of thymidine is replaced with N3
Nucleoside reverse transcriptase inhibitors
1)
2)
3)
1) Thymidine, cytosine, guanine analogues.
2) Phosphorylated by cellular kinases, used by HIV RT preferentially to normal nucleotides.
3) Prevents chain elongation.
Problems with nucleotide RT inhibitors
1)
2)
1) Reduces infection of new cells, but can’t completely eliminate virus
2) Need combination therapy, or resistance emerges
Non-nucleotide RT inhibitors
Do not bind to nucleotide binding site of RT
Are not DNA analogues
Directly inhibit RT via other mechanisms
HIV protease inhibitor mechanism of action
1)
2)
3)
1) Bind tightly to active site of protease.
2) Peptidomimetics, have a close similarity to target amino acid sequence of protease.
3) Protease can’t break protease inhibitor, can’t cleave gag/pol polyprotein, can’t enzymatically mature HIV virion.
Raltegravir
1)
2)
1) An integrase inhibitor (HIV)
2) Blocks integrase strand transfer
Example of a protease inhibitor
Lopinavir
