13396425
| Question | Answer |
| What do the azoles anti-fungals do? | Azoles bind to lanosterol 14-a-demethylase and inhibit the production of ergosterol, causing build-up of toxic methylsterols (cell death/inhibition of growth follows) |
| What size are viruses? | 30 - 350nm in diameter |
| What are the glycoproteins that make up a HIV particle? | gp120, gp41 |
| What process is unique to HIV? | Reverse transcription, a therapeutic target for antivirals (NRTIs/NNRTIs). Makes double-stranded DNA |
| Nucleoside analogue reverse transcriptase inhibitors (NRTIs)? | ddI, ddC, AZT (azidothymidine). AZT is phosphorylated by cellular kinases (like all nucleotides), binds to reverse transcriptase |
| Non-nucleoside reverse transcriptase inhibitors (NNRTIs)? | Efavirenz, nevirapine, etravirine, delaviridine. Different structures, target same site: do not compete with substrate. Can treat with two drugs |
| What happens during maturation of a HIV particle? | Protease cleaves proteins attached to the membrane (enzyme not found in host cell) |
| Protease inhibitors (PI)? | Saquinavir, nefinavir. Dimeric structure, competes with protease |
| Highly Active Anti-Retroviral Therapy (HAART)? | Avoid cross resistance, highly effective at reducing viral load, long asymptomatic phase. Expensive, lifestyle effects, drug interactions, life-long therapy |
| What percentage of people do not clear Hepatitis C after infection? | 85% |
| Hepatitis C virus? | Enormous variability, rapidly mutates. RNA-dependent RNA polymerase. Has protease activity. NS5A: target protein but no enzymatic activity |
| Hepatitis C infection? | 50% develop cirrhosis from high alanine transaminase, leads to liver dysfunction -> liver cancer |
| NS3 protease inhibitors? | Hep C: target polymerase and protease. 1st G: telaprevir, boceprevir - rapidly mutate, genotype 1. 2nd G: simeprevir - potent, can't mutate as easily, more genotypes than 1st G |
| NS5A inhibitors? | Hep C. NS5A: virus RNA replication, virus assembly, not enzymatic, target for antivirals. Inhibitors: bind domain I. 1st G: daclatasvir/ledipasvir - low barrier resistance. 2nd G: in development |
| NS5B inhibitors (RNA polymerase inhibitors)? | Hep C. Target: RNA polymerase. Sofasbuvir (nucleoside analogue), used in every drug combination for HPC |
| Which human herpesviruses belong to which subfamily? | Herpes simplex virus 1 + 2, (HHV1, HHV2) VZV (HHV3): alpha. HHV7, HHV6, CMV (HHV5): beta. KSHV, EBV: gamma |
| Can herpes simplex type 1 cause encephalitis? | Yes in rare occasions - oedema, haemorrhages and necrosis (confined to temporal lobes) |
| What is the lytic phase of herpesvirus? | Productive phase: infects cell, replicates in epithelial cells, leads to cell destruction and release of infectious particles |
| What is the latent phase of herpesvirus? | Non-productive infection: evade immune response, limited gene expression, sits in sensory ganglion, re-emerges at weakened immune system |
| What is LAT? | Gene that is transcriptionally active during latency phase (unusual), helps keep the genome silent as episome in nucleus and prevents apoptosis |
| How many people are infected with HHV1? | 67% of the population and half a billion have genital infection by HSV1 or HSV2, no cure |
| What antivirals can treat herpes? | Acyclovir, valacyclovir, famcyclovir. Val and fam have higher oral bioavailability than acyclovir |
| Explain the action of acyclovir for the treatment of herpes | Lacks ribose moiety of normal guanosine, replaces guanosine. Viral thymidine kinase catalyses ACV to ACV-MonoP, cellular kinases catalyse ACP-MonoP to ACV-TriP -> then replaces guanosine, stops DNA replication -> cell dies |
| Is acyclovir a prodrug? | Yes - it is inactive in normal cells as viral thymidine kinase is absent in normal cells |
| What are the differences between the nucleoside analogues? | Valacyclovir is esterified version of acyclovir, converted by esterases to acyclovir. Famcyclovir is prodrug of penciclovir |
| Is genital herpes common in HIV-infected individuals? | Yes - 70% have genital herpes recurrence (deep ulcerative lesions) |
| Future therapies of herpes? | Helicase-primase inhibitors (inhibit DNA replication - bind in DNA, unwinding) |
| Why are helicase-primase inhibitors promising? | Helicase-primase complex has multiple enzyme activities. Aminothiazolylphenyl-based inhibitors effective (enhance binding of complex to DNA, gets stuck) |
| What is BILS 179 BS? | Alternative to acyclovir in herpes treatment: sticks helicase-primase complex onto DNA so it cannot move/replicate |
| What is neonatal herpes? | Huge infection, encephalitis, cognitive impairment, organ dysfunction, death. From vertical transmission (mother to baby) |
| What is post-herpetic neuralgia? | Linked to HHV3: VZV when reappeared as shingles in elderly. Damaged nerve endings, misfiring of neurons = excruciating pain |
| IV acyclovir use in management of Herpes zoster? | 10mg/kg 3x day: crystalluria in patients with renal impairments; CNS disturbances |
| Valacyclovir in management of Herpes zoster? | 1000mg 3x day: acute hypersensitivity |
| Famciclovir in Herpes zoster? | 500mg every 8 hours, 7 days: headache, nausea |
| New antivirals against VZV? | Cidofovir derivatives: inhibits viral DNA polymerase. Only needs 2 phosphorylation steps to become active, acyclovir needs 3 (first by viral TK). CMX001: lipid ester derivative of cidofovir |
| What is ASP2151? | A helicase primase inhibitor for VZV: more potent than acyclovir, more specific for VZV than BILS 179 |
| What are bicyclic pyrimidine nucleoside analogues (BCNAs)? | Potent VZV treatment: BCNAs converted to monoP and diP by VZV thymidine kinase (double hit). Incorporated into viral DNA, stops DNA replication, cell dies |
| What are the forms of Kaposi's sarcoma-associated herpesvirus? | Classical KS (Europe), Endemic (Africa, HIV-ve), Post-transplant KS, HIV-assocaited KS |
| Why is there no current treatment for KSHV? | Thymidine kinase in gamma is different to alpha and betas (acyclovir doesn't get phosphorylated). Therapeutics target HIV with HAART, conventional chemotherapy used |
| What are some novel antivirals for KSHV? | VEGF inhibitors (vascular tumour): bevazicumab is a humanised monoclonal antibody, blocks VEGF-A. Very expensive. Imatinib: blocks tyrosine kinase active site of C-kit (upregulated by virus to inhibit apoptosis) |
| Influenza virus? | Negative stranded RNA segmented virus. Orthomyxoviridae family (A, B and C). Each type has genes which encode for M2 protein |
| Which subfamily of influenza virus infects what? | A = humans, pigs, birds, horses, aquatic mammals (can cause global pandemics). B = humans only (no pandemics). C = humans and pigs (no pandemics) |
| Morphology of influenza virus? | Pleomorphic, 80 - 120 nm. 3 membrane proteins: Hemagglutinin (HA), trimer; Neuraminidase (NA), tetramer, head and stalk; M2, tetramer. Matrix underneath membrane |
| How does influenza virus attach to host cell? | Hemagglutinin binds sialic acid on surface of epithelial cells lining respiratory tract, virus internalised |
| How does influenza virus enter the cell? | Virus envelope fuses with endosomal membrane due to low pH of endosome. M2 protein acts as ion channel = influx of H+, matrix breaks down, segments released into cell |
| How does influenza virus get released? | Released virus wants to infect cells but HA on released virus can bind sialic acid on old cell. NA cleaves old sialic acid, allows virus to infect new cells by HA binding to sialic acid |
| What is antigenic drift? | The incorporation of single nucleotide changes: new virus particles released from infected cells different from the ones that went in |
| What is antigenic shift? | When two different viruses infect he same cell: segments able to mix around, virus comes out as a combination of the two sets of segments |
| What do current anti-influenza therapeutics target? | The stage of endosome escape and the stage of release (NA) |
| What are adamantanes? | Amantadine and rimantadine: influenza antivirals. Block M2 activity, effective at low concentrations. Rim has methyl group, less side effects, improved efficacy. Cheap + effective but must be administered before day 2 of infection |
| What is the problem with adamantanes? | Strains became resistant after 30 years (mutations within M2 channel), now all strains resistant and inhibitor not used |
| What is zanamivir? | Influenza antiviral (aerosol): high affinity for NA (mimic sialic acid). Has hydroxyl removed, addition of Guanidino group at C4. Need to take within first 2 days |
| What is aseltamivir? | Influenza antiviral: tablet. Mimics sialic acid, contains influenza infection. Need to take within first 2 days |
| Why should Relenza and Tamiflu not encounter resistance? | As NA must maintain its ability to bind sialic acid for virus viability, NA is essential for infectivity. A virus that no longer binds these drugs will not bind SA. However, some resistant strains emerged (H3N2) |
| What is ribavirin? | A guanosine (purine) analogue, modified by kinases to generate ribavirin-triP, trapped inside cells. FDA-approved for Hepatitis C and Respiratory syncytial virus |
| Ribavirin role in rabies? | 3 patients survived rabies: ribavirin used in combination, ketamine-induced coma. Milwaukee, hasn't been reproduced |
| How do Hepatitis C and Human respiratory syncytial virus differ? | Hep C: (+) sense RNA, latent, hepatic. HRSV: (-) sense RNA, lytic, respiratory. |
| Hepatitis C | Flaviviridae family, 200 million infected. Blood transmission: needles, sex. Treatment until recently: ribavirin + interferon, 56% response |
| Human Respiratory Syncytial Virus | Negative stranded paramyxovirus, can be fatal. Ribavirin aerosol in young infants, very expensive |
| How does ribavirin work? | 3 mechanisms: inhibition of IMPDH by ribavirin 5-monoP, error catastrophe in RNA replication, inhibition of RNA polymerisation by the RdRp |
| Ribavirin mechanism 1 (IMPDH inhibition)? | IMPDH enzyme converts IMP to XMP (precursor for production of GTP, which is required for RNA and DNA synthesis). Ribavirin = competitive inhibitor of IMPDH, reduce GTP pools, reduce RNA synthesis |
| Ribavirin mechanism 2 (error catastrophe)? | RdRp (viral polymerase) carries out genome replication. 1 mistake in 10,000 nts. Ribavirin incorporated in place of G or A nts: 50% chance of error, error rate too high = lethal |
| Ribavirin mechanism 3 (inhibition of RNA polymerisation by RdRp, Hepatitis C mechanism)? | Ribavirin fits in polymerase active site, mimics an rNTP (RNA nts). Binds polymerase, slows life cycle, immune response able to take over |
| What are the negatives of ribavirin treatment? | Not good efficacy as monotherapy. Haemolytic anaemia because of phosphorylating nature. Stored in cells for v long time |
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