Antivirals Flashcards
(17 cards)
How do we treat viral diseases
1) by mitigation of symptoms (could be by anti-inflammatory drugs or pain relief)
2) curative treatment which is antiviral chemotherapy
Antiviral chemotherapy - what is it
this is the treatment of viral infections which block viral infection and viral replication
ANY step in viral replication can be targeted
What is chemotherapeutic index
the relative toxicity of the host vs the relative toxicity of the virus
the drug must me more toxic to the virus than the host and the more toxic the virus is the better
Outline the general life cycle of a virus
1) virus binds to cell surface receptor and enter the cell
2) replication of genetic material (transcription)
3) production of new proteins (translation)
4) assembly of the new virus
5) the release of the new virus
Effective targeting of antivirals
Type of virus has major implications for how the type of treatments possible
E.g. RNA vs DNA viruses
Mechanism of replication
Speed of evolution
Success of antiviral drugs lies in their specificity (NEED IT TO BE SPECIFIC)
Antiviral drug discovery
Discovery of antivirals is largely fortuitous
Large screening efforts mostly failed to identify antivirals (broad or specific)
Many antivirals are the result of rational design
Rational design of antivirals
Understanding of key steps in viral replication
Structural information for targets
Computer-aided drug design
Targeting viral replication – Nucleoside analogues
Many viruses use virally encoded enzymes to replicate viral nucleic acids preferentially
These are different enough to human enzymes to provide a basis for specificity
Most nucleoside analogues target RNA polymerases
Many broadly acting antivirals are nucleoside analogues
Acyclovir – acycloguanosine
Active against range of DNA viruses: HSV, Varicella-Zoster, Epstein-Barr, HCMV
Mimics guanosine in DNA replication
Results in premature chain termination when incorporated into DNA
Competitively inhibits DNA polymerase
Higher CMV action achieved by ganciclovir
Valaciclovir and valganciclovir – prodrugs (can administer in a different way)
Ribavirin
Acts against both RNA and DNA viruses
It functions as a Guanosine analogue
Variety of proposed mechanisms:
Processed by inosine triphosphate pyrophosphatase – results in reduced activity – potentiates mutagenesis in HCV (hepatitis c virus)
Inhibits inosine monophosphate dehydrogenase – depletes cellular pools of GTP
Orientation of amide group can make it look like adenosine or guanosine (so can bind to adenosine or cytosine) – leads to mutagenesis
10-fold increase in RNA virus mutagenesis, 99% loss in virus infectivity after a single round of infection
Targeting viral replication – non-nucleoside analogues
Bind to allosteric sites on target proteins
Unlike nucleoside analogues, tend to be virus specific
Widely employed in anti-HIV therapies
Target reverse transcriptase
Non-nucleoside reverse transcriptase inhibitors – AKA Efavirenz
Common binding pocket for most NNRTIs
Prevents reverse transcription of viral ssRNA to dsDNA
First-line highly active antiretroviral therapy drug
Drug analogues needed due to resistance
HIV antivirals - what is inhibited
So the drugs Ibalizuma and Fostemsavir are compounds that act on hiv binding to cd4 prevent the binding so if this is interrupted we cant get viral replication
Enfuviritide which is an inhibitor of the fusion of the viral and host membranes
and Lencapavir targets the capsid protein which inhibits the fusion of the viral and host membranes which prevents viral coating from occurring so presents delivery of the viral genome into the cell
Abacavir (nucleoside analogue) and Efavirenz (non nucleoside analogue) so reverse transcription stage
Dolutegravir and Raltegravir = block integration by directly targeting HIV one integrase proteine
Saquinavir and Ritonavir = can interfere with final maturation stage
HIV antivirals
Almost every step of the infection cycle can be targeted
( HIV medications have become ) Effective enough that most individuals can live a mostly normal life
Great example of what can happen when policy, economics & public interest align
Significantly reduces HIV-related mortality and morbidity
Anti-influenza drugs
High variability due to antigenic drift/shift complicates entry inhibitors
Requires a site of action conserved across all strains
Neuraminidase active site
Importance of neuraminidase
binds to sialic acid
engulfing virus
uncoating and viral replication
Neuraminidase = one of the two proteins that are displayed on the surface of the influenza virion
drugs that target neuraminidase - Zanamivir & Oseltamivir
Both Developed through rational drug design based on X-ray structures
Zanamivir requires negative charge for activity, but this blocks oral uptake
Provided directly to respiratory tract via inhalation (has some side effects)
Oseltamivir administered as a prodrug, processed in liver
