Coronaviruses Flashcards
1
Q
Describe the clinical course of SARS (02-04)
A
- initial flu-like symptoms, fever, fatigue
- nonproductive cough
- 50% of patients required mechanical ventilation
- lymphopenia
- 10% case fatality rate (higher in men, milder in children
2
Q
What is ACE2 and its role in Coronainfections?
A
- Angiotensin converting enzyme
- important for crossing species (SARS is zoonosis)
- spike protein binds to it
3
Q
Coronavirus biology
A
- (+)ssRNA virus
- four genera -> SARS, MERS, SAR-CoV 2 are all β Coronaviruses
- monocystronic transcription (Pol falls off after one gene)
- TRS sequences function as jumpers to enable discontinues transcription
4
Q
MERS (12)
A
- sequence identity of 46% with SARS
- case fatality of 36%
- transmission trough close contact
- dromedary camels are intermediate host
5
Q
SARS-CoV 2 - facts
A
- sequence identity with SARS (77.5%) and MERS (50%)
- respiratory symptoms
- transmission via aerosols
- case fatality age dependent up to 10%
- zoonosis
6
Q
SARS-CoV 2 prophylaxis
A
- vaccines
- 2 mRNA
- 3 protein
- 2 vector (Astra)
- 1 inactivated
7
Q
Coronavirus entry inhibitors
A
- APN01: recombinant hACE2; high affinity to SARS-CoV 2 S; competes with membrane ACE2 for virus binding -> lowers viremia; reduces harmful inflammation in lungs
- mABs (like in Ebola)
- 5 human mABs or mAB cocktails in clinics argentine spike protein
- suitable early in infection
- don’t cover all variants of concern
8
Q
Explain the coronavirus entry
A
- spike protein needs two proteolytic cleavages
- at S1/S2 during virus release and to free the S2‘ site
- at S2‘ to expose the fusion peptide
9
Q
Coronavirus immune modulators
A
- Covid 19 late phase is driven by aggressive immune response
- IL-1 receptor blocker
- unspecif anti-inflammatory treatment (also used in rheumatoid arthritis) - JAK/STAT inhibitors
- targets later step than IL-1 blocker
- was withdrawn
10
Q
Coronavirus replication inhibitors
A
- coronavirus RdRp encodes a proofreading activity (ExoN of nsp14) -> incorporation of analogues is difficult
- Remdesivir (broad spectrum) only stalls after three nucleotides -> works
- Molnupiravir (broad spectrum) forms stable bonds with G or A in catalytic center -> prevents proofreading (no marketing authorisation)
11
Q
Coronavirus protease
A
- two possible targets: TMPRSS2 (activates spike protein), main protease
- main protein:
- cleaves large polyprotein (PP1ab)
- 3 domains; I + II have chymotrypsin like fold and activity (3CLpro)
- 3CLpro is dimer; protomer A is active, protomer B is inactive
- cleaves with conserved Gln at position P1
12
Q
Coronavirus protease inhibitors
A
- peptidomimics inhibit the protease activity
- Nirmertralvir based on a lead compound discovered during SARS, oral admission possible
- Paxlovid -> combination of Nirmertralvir and Ritonavir
- exhibits potent pan-corona activity in vitro
- Rionavir slows down Nirmertralvir breakdown
13
Q
What is drug repositioning?
A
- trying to find a drug that is already approved for other diseases to use it for another treatment too
