Antivirals Flashcards
Virus characteristics
non-cellular. Obligate intracellular parasites, require host to replicate. RNA or DNA genome, can be enveloped by lipid membrane, 20-350nm diameter.
Simple life cycle of virus
Enter host cell. RNA/protein synthesis to replicate genome. Further protein synthesis to assemble new inflectional viral particles. Release new viral particles from cell for further infection.
Functions of host cell
The raw materials for viral biomolecule synthesis (amino acids, nucleotides). Machinery for protein synthesis. Protective membrane. Transport around cell.
Properties of antiviral drugs
Cell membrane permeable. Selective against cellular targets. inhibit virus-encoding proteins or viral-spefic functions. Target a critical stage of virus life. Little resistance potential.
HIV structure
gp120 surface glycoprotein, gp41 transmembrane glycoprotein, p17 matrix antigen, p24 capsid antigen enclosing genome, unique reverse transcriptase protease and integrase enzymes.
Pathology of HIV
Qualitative and quantitative decline in CD4+ lymphocytes. Infects CD4 cells = dendritic cells, T-lymphocytes and macrophages. CD4=glycoprotein
Course of HIV infection
primary phase illness = high viraemia, decreasing CD4 count. Asymptomatic phase =(10yrs+) viraemia stays at set point and steady decrease in CD4, AIDS phase = great increase in viraemia, drop in CD4 count.
HIV therapy
HAART. Nucleoside analogue reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors, Protease inhibitors. 2NRTI and 1PI or NNRTI. 99% reduction in viraemia in 8 weeks. Can interrupt treatment and can manipulate Rx.
Reactions in HIV cell
Reverse transcriptase = create double stranded DNA copy of single stranded RNA genome. Integrase = ingrate DNA into nucleus. Maturation of new virons to become infectious = proteases.
NRTI mode of action
Selective reverse transcriptase inhibitors. Needs to be phosphorylated by cellular kinases. Act as analogue to endogenous substrate thymidine triphosphate but drug lacks 3’-hydroxyl group preventing phosphodiester bonding. Incoperatd into chain at 5” area. Product is chain terminator so abnormal DNA created.
NRTI problems
Resistance within patients, virus replication recovers as RT mutates. Life long treatment as memory cells act as reservoir for virus. Toxicity: (gamma DNA of mitochondria particular target and cause of ADR ) GI upset, anaemia and other blood disorders, dizziness, insomnia, headache.
NRTI examples
Azidothymidine (AZT/Zidovudine), Deoxycytidine, Adenosine.
NNRTI
Bind to allosteric site on enzyme but various structures within group. Do not compete with NRTI so can use in combo.
Examples of NNRTI
Etravirine, Efavirenz.
Enzymes in HIV
All from Pol gene on genome. reverse transcriptase, protease, integrase.
Proteins in HIV iron maturaion
Gag and Gag-Pol. Cleave when virus buds off . Need protease to cleave.
Protease inhibitors for HIV and example
Competitive inhibition of aspartyl protease. This enzyme is needed to create functioning proteins from poly proteins. Inhibition prevents production of mature viral particles. Needs to be membrane permeable. e.g: Nelfinavir, Saquinavir
Hepatitis C pathology
7 different genotypes with different toxicities. 15% get initial acute infection then clearance. 85% get chronic infection of which 50% get mild hepatitis with normal ALT and 50% get elevated ALT, cirrhosis and increase risk of heptatocellular carcinoma.
Life cycle targets for HCV
Translation and polyprotein processing, need protease and helicase enzymes = NS3 inhibitors. RNA replication with RNA-dependent RNA-polymerase (5B) 5A know enzyme = NS5A/NS5B inhibitors.
NS3 inhibitors types
Protease inhibitors. 1st gen are potent but high resistance, specific to genotype 1 e.g. telaprevir. 2nd gen potent, less resistance, wider genome spectrum e.g. simprevir.
NS5A
NS5A: Not enzyme but acts in RNA replication, viral assembly, interaction with RNA and cellular factors/proteins. Target is in domain 1 of protein.
NS5A inhibitors
e.g. daclatasvir. VERY POTENT even at picomolar levels. 1st gen risk resistance high. 2nd gen have broader genome spectrum.
NS5B inhibitors
Inhibit RNA polymerase. e.g. sofosbuvir.
NICE guideline for genotype 1
12 weeks. Sofosbuvir (NS5Bi) and NS5Ai Velapatasvir. get clearance of virus.
Alpha herpes simplex viruses and pathology
1,2,3. HSV1 = oral and ocular (cold-sores).
HSV2 = genital.
HSV3 = chickenpox & shingles/Varicella Zoster
Beta herpes simplex viruses
5,6,7
Gamma herpes simplex viruses and pathology
4,8. ONCOGENIC. HSV4 = Epstein-Barr virus, B cell tumours. HSV8 = Kaposi’s sarcoma herpes virus
Varicella Zoster
HSV3
Life cycle of HSV
Latent = viral capside is in epithelial cells, travels to CNS ganglion up afferent axon. Quinescent stage, transcriptionally silent, no immune response. Lytic = stimulus re-activates silent virus. Virons release and move back down axon and symptoms seen at original infection site.
HSV1 and HSV2 treatment
Acyclovir, Valacyclovir (acyclovir derivative), Famcyclovir