Introduction to Antivirals Flashcards
Antivirals
- Antiviral agents are inhibitors of viral replication
- Since viral replication is associated with metabolism of the host cells, it is very difficult to develop antivirals that only attack the virus but not the host cell
- oxicities and Resistance
Potential Sites for Antivirals
- Viral attachment, penetration and uncoating
- Reverse Transcription (retroviruses)
- Viral replication and integration
- Transcription and Translation
- Viral assembly
Inhibitors of Viral Attachment
- Viral specific spikes interact with a specific receptor on the host cell
- This interaction could be blocked by neutralizing antibodies or other inhibitors
Inhibitors of Viral Attachment - HIV
•Maraviroc
-HIV-1 coreceptor CCR5
•Enfuvirtide
-HIV-1 gp41
Inhibitors of Cell Penetration and Uncoating
- Two related synthetic amines, Amantadine and Rimantadine
- Prevent uncoating or RNA transcription, if used early in infection
- Low doses may also inhibit viral assembly
- Both the agents are taken orally and have low toxicities
- Active against Influenza A but not B
- Influenza A virus became resistant to both the agents during treatment, Not used anymore
Prophylaxis: 70% effective if given daily during influenza outbreaks
Mechanism: They target the M2 (matrix) protein
Toxicity: CNS complaints, minor nervousness and light-headedness
Inhibitors of Cell Penetration and Uncoating Resistance
•Resistance requires only a single amino acid change in transmembrane protein
Inhibitors of Viral Release - Neuraminidase Inhibitors: Oseltamivir
- Oseltamivir (Tamiflu) selectively inhibits the neuraminidase of influenza viruses - Competitive inhibitor towards sialic acid
- Orally administered
- Reduce influenza symptoms and shorten the course of illness by 1 to 1.5 days
- Active against both influenza A and B
- Recommended above 2 weeks of age and above
- Common adversity: nausea, vomiting, diarrhea, abdominal pain
- Rare adverse reactions: hepatitis, elevated liver enzymes, rash, allergy, anaphylaxis
Inhibitors of Viral Release - Neuraminidase Inhibitors: Zanamivir
selectively inhibits the neuraminidase of influenza viruses - Competitive inhibitor towards sialic acid
- Orally administered
- Reduce influenza symptoms and shorten the course of illness by 1 to 1.5 days
- Active against both influenza A and B
- given as inhalation powder for oral inhalation, 7 years of age and above
- Common adversity: nausea, vomiting, diarrhea, abdominal pain
- Rare adverse reactions: hepatitis elevated liver enzymes, rash, allergy, anaphylaxis
Inhibitors of Nucleic Acid Synthesis
- Most antivirals are nucleoside analogs that interfere with viral DNA and RNA syntheses
- Serve as chain terminators after incorporation into the nucleic acids
- Most specific agents work on virus specific nucleic acid polymerases or transcriptases
Inhibitors of Nucleic Acid Synthesis: Zidovudine (ZDV) or AZT
Inhibitors of Nucleic Acid Synthesis: Adenine Arabinoside (Vidarabine)
- Purine, inhibits DNA polymerase
- Phosphorylated to its active form intracellularly, 15 to 30 times more
- Susceptible to herpes DNA polymerases than cellular DNA polymerases
- Less toxic than others
- Intravenous administration reduces the mortality of herpes encephalitis
- Useful in the treatment of neonatal herpes infection and herpes zoster in immunocompromised patients
- Used in the treatment of herpes infection of eye
Inhibitors of Nucleic Acid Synthesis: Acyclovir
- Acycloguanosine
- Very active against replicating herpes simplex virus (HSV)
- Phosphorylates to monophosphate form by virus specific thymidine kinase limiting the presence of the derivative to virus infected cells
- Further phosphorylates to triphosphate form by cellular kinase to inhibit viral DNA polymerase 100 fold greater than cellular DNA polymerase
- It causes termination of herpes DNA elongation
- Little toxicity for host cells
Acyclovir and CMV
•CMV is resistant to acyclovir because it kinase is unable to phosphorylate acyclovir
Acyclovir and VZV and EBV
•Less effective against Varicella-Zoster Virus (VZV) and Epstein-Barr virus (EBV)
Acyclovir Preparations
- Available in topical, oral, and intravenous preparation
- Oral therapy is effective in primary oral and genital herpes simplex infection
- Prophylactic use is helpful in frequent recurrences of herpes
- Intravenous is used to manage severe genital herpes and VZV in immunocompromised and burn patients