covid assignment Flashcards
The coronavirus family has several sub-types
a. How many sub-types cause human disease?
b. How many sub types cause serious human disease?
c. What are the sub-types in part b?
a) 7
b) 3
c) SARS, MERS, COVID
What are the pre-existing medical conditions associated with severe illness due to
COVID
Diabetes (type II) Heart disease (heart attack, coronary artery disease, cardiomyopathies) Hypertension COPD Chronic kidney disease Cancer Immunocompromised state Sickle cell disease Obesity
The initial entry of the COVID virus into human cells involves endosome formation.
a. What viral protein is involved in this process?
b. What human protein is involved in this process?
c. Describe how the interaction between these two proteins creates an endosome
d. What is the normal function of the protein in part b?
e. What two processes disrupt the function of this protein during COVID infection?
a) spike
b) ace2
c) diagram
d) Enzyme that converts angiotensin II (angiotensin (1-8)) into angiotensin (1-7)
e) Binding of spike protein to ACE2 blocks normal ACE2 catalysis; enclosure in the
endosomes removes ACE2 from surface of cells
Describe the normal operation of the renin angiotensin system in the body.
diagram
The COVID viruses uses a method of protein translation that is common to many viruses.
a. What is this method of protein translation?
b. What general class of enzyme does the virus need in order to use this method of
translation, and what kind of chemical reaction do they carry out?
c. Name 3 families of enzyme that make up the class of enzymes in part b.
d. How do these enzymes “know” which chemical bonds to perform their reactions
on?
e. Name the 2 enzymes used by COVID for this purpose.
a) Single polyprotein is translated by the human ribosome using viral RNA
template. Viral proteases cut this polyprotein into the actual (smaller) viral
proteins
b) Proteases. These enzymes hydrolyze amide bonds, and can sometimes form
amide bonds
c) Serine proteases, cysteine proteases, aspartyl proteases
d) The shape and chemical properties of the active site in the enzyme is
complimentary to the sequence of amino acids close to the target amide bond.
When a peptide with the proper sequence of side chains fits inside the active
site, the catalytic machinery will be close enough to the target amide bond to
carry out the reaction. Only peptides with the right amino acid sequence can fit
properly in the active site. Most protease have special “pockets” that each side
chain fits into. + diagram i guess
e) 3CL protease; papain-like protease
One of the first drugs used to treat COVID infections was hydroxychloroquine.
a. What viral process does this drug target?
b. How does this drug block viral infection?
c. Describe how this drug was discovered.
d. How effective is this drug in preventing the spread of COVID?
a) Endosome opening
b) The endosomes open when the pH inside the endosomes falls (becomes acidic).
Hydroxychloroquine is a base and neutralizes the acid inside the endosomes.
c) Researchers in a lab were studying endosome formation associated with
different types of viral infection. As part of this research, they were investigating
pH changes during endosome opening and found that the endosomes opened
when the pH inside decreased. To test this observation, they added large
amounts of different bases to cells that were infected with viruses. These
experiments showed that the endosomes would not open if enough base was
present. One of the bases they used was hydroxychloroquine. Because the
endosomes under study involved viruses, the researchers claimed that
hydroxychloroquine had anti-viral activity. Later other researchers tested
6 hydroxychloroquine on animals and found that large doses could inhibit viral
growth. (risks outweigh benefits)
d) Not very effective. Recently the WHO and FDA have advised doctors to stop
using it for COVID because the drug does not work, and the side effects can be
dangerous.
The 3CL protease enzyme in COVID is required for viral replication.
a. What family of enzymes does this molecule belong?
b. What is the general structure of the active site of this enzyme?
c. What is the function of each of the parts in the active site?
d. What is the mechanism by which the COVID protease hydrolyzes amide bonds?
e. What part of this mechanism is used to design inhibitors using rational drug
design?
f. What type of inhibition does it produce?
g. What is the general class of the drug created using this method?
h. List 2 advantages of designing drugs this way.N
a) Cysteine proteases.
b) diagram
c) Cys = nucleophile; His = base; oxyanion hole stabilizes negatively charged
oxygens
d) diagram
e) Transition state
f) Covalent (reversible) inhibition
g) Transition state mimic
h) Enzymes binds very tightly to transition states so should bind well to the drug;
can design inhibitor knowing the reaction mechanism
