46. Mechanism of Antivirals Flashcards
Use of anti-virals
• Treatment of acute infection
- Influenza ; Chickenpox; herpes infections -(aciclovir)
• Treatment of chronic infection:
- HCV, HBV, HIV (numerous different agents)
•Post-exposure prophylaxis and preventing infection:
- HIV (PEP)
•Pre-exposure prophylaxis:
- HIV (PrEP)
•Prophylaxis for reactivated infection: e.g. in transplantation
- CMV (ganciclovir, foscarnet)
Principles of Anti-Virals
as Therapeutic Agents
Selective Toxicity
- Due to the differences in structure and metabolic pathways between host and pathogen
- Harm microorganisms, not the host
- Target in microbe, not host (if possible)
- Difficult for viruses (intracellular), fungi and parasites
- Variation between microbes
Why is it so difficult to develop effective, non-toxic anti-viral drugs ?
- Viruses enter cells using cellular receptors which may have other functions
- Viruses must replicate inside cells – obligate intracellular parasites
- Viruses take over the host cell replicative machinery
- Viruses have high mutation rate - quasispecies
- Anti-virals must be selective in their toxicity ~ i.e. exert their action only on infected cells
- Some viruses are able to remain in a latent state e.g. herpes, HPV
- Some viruses are able to integrate their genetic material into host cells ~ e.g. HIV
Virus Life Cycle
- Recognition
- Attachment
OR Fusion - Penetration
- Uncoating
- Transcription
- Protein Synthesis
- Replication
- Assembly
- Lysis and release
OR - Envelopment
- Budding and release
Modes of action of selected anti-virals
- Preventing virus adsorption onto host cell
- Preventing penetration
- Preventing viral nucleic acid replication (nucleoside analogues)
- Preventing maturation of virus
- Preventing virus release
Herpers viruses and drugs for treatment
- Herpes simplex (HSV),
- Varicella Zoster Virus (VZV)
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
•aciclovir
- IV/oral/topical
- For HSV, VZV
- treatment/prophylaxis
- CMV/EBV prophylaxis
•ganciclovir
- IV/oral
- For CMV
• Foscarnet
- IV/local application
- For CMV
•cidofovir
- IV for CMV
Selective toxicity of aciclovir
- Aciclovir is activated to active drug
- Substantially more in infected cells
Requires 2 viral enzymes
= selectively activate ACV
= selectively inhibited
Accounts for low toxicity
Ganciclovir
Active for CMV
- reactivated infection or prophylaxis in organ transplant recipients
- congenital infection in newborn
- retinitis in immunosuppressed
•Structurally similar to aciclovir
•CMV does not encode TK but has UL97 kinase
•Inhibits CMV DNA polymerase
Foscarnet
- Selectively inhibits viral DNA/RNA polymerases and RTs
- No reactivation required
- Binds pyrophosphate binding site – a structural mimic used for CMV infection in the immunocompromised ~ e.g. pneumonia in solid organ and bone marrow transplants.
- May be used because of ganciclovir resistance (TK mutants)
Cidofovir
- Chain terminator - targets DNA polymerase
- Competes with dCTP
- Monophosphate nucleotide analog
- Prodrug – phosphorylated by cellular kinases to di-phosphate
- Drug active against CMV; but MUCH MORE nephrotoxic
- Treatment of retinitis in HIV disease
Resistance to anti-virals in Herpes viruses
Two main mechanisms
- Thymidine Kinase mutants
- DNA polymerase mutants
- If occurs in TK, drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir)
- If occurs in DNA polymerase, all drugs rendered less effective
- VERY RARE in immune competent patients (low viral load)
Structural features of HIV
•ds RNA genome •Viral envelope •reverse transcriptase •Nucleocapsid protein Gag p24 • Membrane-associated matrix protein Gag 17 •Envelope protein, gp120 with transmembrane gp41
Steps in the life cycle of HIV
1) Attachment with binding
of viral gp120 via CD4 and CCRX
2) Reverse transcription of RNA into dsDNA
3) Integration into host chromosome of proviral DNA
4) Transcription of viral genes
5) Translation of viral mRNA into viral proteins
6) Virus assembly and release by budding
7) Post-release maturation
