Treatment/Prevention/Control Viral Diseases Flashcards
Possible targets for Antiviral chemotherapy in Veterinary medicine.
Attachment of virion to cell receptor - Receptor analogs
Uncoating - Rimantadine
Primary transcription from viral genome- Transcriptase inhibitors
Reverse transcription Zidovuldine -AZT
Regulation of transcription Lentivirus tat inhibitors
Replication of viral DNA genome - Acycloguanoside Acyclovir
Replication of viral RNA genome Replicase inhibitors
Post-translational cleavage of proteins- PRotease inhibitors
Translation of viral RNA into protein - Interferons
Processing of RNA transcripts - Ribavirin
Name general properties of Acyclovir
- used for herpesvirus
- Administered as prodrug, then the viral enzymes in the infected host convert it to the active form which then interferes with virus replication.
- Used in treatment of : Herpesvirus infections in humans, Feline herpesvirus 1 induced corneal ulcers, Equine herpesvirus-1 induced encephalomyelitis
- It is a synthetic nuceloside analog of deoxyguanosine
What is the mechanism of Antiviral effect of Acyclovir
Herpes Thymidine Kinase or TK gets Acyclovir and convertes it to acyclovir monophosphate. Then host cell enzymes add two phosphates, using cellular kinase GMPK and NDPK. The cleavage of 2 phosphates fro the acylcovir triphosphate by the herpes simplex’s own enzymes to form acyclovir monophosphate. The herpes simplex’s DNA polymerase enzymes incorporates the acyclovir monophosphate into the growing DNA strand as if it were 2-deoxyguanosine monophosphate (a “G” base). You stop the growing viral DNA chain. Also Competitive inhibition of viral DNA polymerase; the Acyclovir Triphosphates compete with dGFPs for viral DNA polymerase.
Acylovir is nontoxic to the host cell. Name some ways that herpesvirus are resistance to Acyclovir?
Absent production of viral thymidine kinase due to mutations in the virus genome
Partial decrease in the production of viral thymidine kinase
Altered viral thymidine kinase substrate specificity that results in phosphorylation of thymidine but not acyclovir TK altered mutants
Mutations in viral DNA polymerase that causes a decreased binding of acyclovir triphosphate to viral DNA polymerase
Amantadine is a synthetic tricyclic amine of the adamantane family. What kind of virus does it inhibit replication of?
Influenza A viruses by blocking uncoating of the virus.
Acts as both antiviral and anti-parkinsons drug
What are the important structures of the influenza virus?
M2 Ion channel and the M1 Matrix protein
Explain the process of uncoating in the Influenza Virus in host cell cytoplasm.
As the endosomal vesicles that contain the virus particles move towards the cell nucleus, their pH drops, when the endosomal pH reaches the 5.0 the viral HA protein undergoes a conformational rearrangement which release the viral RNA into the cytoplasm. They are then transported into the cell nucleus were viral RNA replication occurs. In the influenza virion the viral RNAs are bound to a number of viral proteins including the M1 protein. This M1 protein forms the shell that underlies the lipid membrane of the virion. If the Viral RNAs are bound to M1 protein they cannot enter the nucleus. Viral M2 protein forms a channel in the membrane that actively pumps protons from the endosome into the interior of the virion these protons lower the pH in the interior of the virion releasing the viral RNAs from M1 proteins.
Mechanism of Antiviral effect of Amantadine
M2 ion channel is the target of the antiviral Amantadine, these clog the channel and prevent it from pumping protons into the virion. The presence of amantadine, viral RNAs remain bound to M1 and cannot enter the nucleus. Virus replication is inhibited. Resistance to amantadine occurs by changes in amino acids that line the M2 channel. These changes prevent the drug from plugging the channel.
What else can can pH changes that result from M2 inhibition alter?
Alters the conformation of hemagglutinin during its intracellular transport later in replication and thus block viral assembly also.
name some Neuraminidase Inhibitors
Synthesized by Influenza A and B viruses, Oseltamirvir (tamiflu) Laninamirvir, Zanamirvir, Peramirvir
Name the 2 major membrane glycoproteins found on the surface of influenza viruses
Neuraminidase NA, and Hemagglutinin HA
What is NA used for in influenza virus? What makes it critical for it?
Ha of influenza virus binds to receptors containing sialic acid on host cell membrane. After budding, HA of progeny influenza virions are still bound to sialic acid, containing receptors on infected host cell surface. NA present on virus will cleave the sialic acid containing cell surface receptors and release HA. The virus is freed from the infected cell. NA is thus critical in cell to cell spread of influenza viruses
Important note from Dr. Ghosh
NA inhibitors do not interfere with replication, they of influenza viruses, but prevent the release of new viruses from the host cell, which slows the spread.
What does NA inhibitors allow the host to do?
NA inhibition prevents the release of viruses and spread of infection as the HA of a the virus is still bound/attached to the sialic acid containing receptors on surface of already infected host cell. Inhibition of neuraminidase therefore slows virus spread giving the immune system the opportunity to catch up and mediate virus clearance.
What are the targets for Anti-retroviral therapy?
inhibit fusion, inhibit integrate, Inhibit reverse transcriptase, Inhibit protease
Name two Nucleoside analog Reverse Transcriptase inhibitors NRTIs?
Zidoovudine ZDV or AZT, Asidothymidine , ddI, Didanosine
What nucleoside analog is ZDV/AZT belong to?
Nucleoside analog of thymine. Resembles the deoxyribonucleotide containing the base thymine.
How does AZT/ZDV WORK?
AZT/ZDV is phosphorylated by kinases prsent in host cell to AZT triphosphate, since it resembles thymine deoxyribonucleotide triphosphate the reverse transcriptase cleaves two phosphates and inserts AZT monophosphate into the cDNA that is being synthesized from viral RNA. Two things happen, Competitive inhibition of Reverse transcriptase activity: AZT triphosphate competes with thymine deoxyribonucleotide triphosphate. and Insertion pf AZT monophosphate into cDNA blocks the growth of the cDNA being transcribed from the viral RNA by reverse transcriptase.
