Lecture 16 - Structure Activity of Antivirals

Question 1

Key enzymes in HIV?

Answer 1

protease

reverse transcriptase

integrase

Question 2

What are nucleoside reverse transcriptase inhibitors?

Answer 2

they mimic the natural nucleosides that are incorporated into the double helix chain formation of DNA-RNA and DNA

Question 3

What type of drugs are nucleoside reverse transcriptase inhibitors?

Answer 3

prodrugs metabolised to give non-functional nucleotides

Question 4

What happens when NRTIs are incorporated into the growing chain?

Answer 4

it causes chain termination

Question 5

What does chain termination cause?

Answer 5

no more HIV can be made and CD4 cells are not further compromised

Question 6

What happens when a nucleoside is phosphorylated?

Answer 6

it becomes a nucleotide

there are 3 phosphate groups required for the molecule to be incorporated into the growing chain

Question 7

Examples of NRTIs?

Answer 7

deoxythymidine

zidovidine

Question 8

What is the key part of an NRTI molecule?

Answer 8

the azide

Question 9

What is required to make the growing chain?

Answer 9

a neighbouring hydroxyl group from another nucleosides, attacks and makes the growing chain

Question 10

Further examples of NRTIs?

Answer 10

lamivudine (epivir)

zalcitabine (Hivid)

stavudine (Zerit)

abacavir (Ziagen)

didanosine (Videx)

emtricitabine (emtriva)

Question 11

What are the two targets of NRTIs?

Answer 11

protease and reverse transcriptase

Question 12

What is remdesivir?

Answer 12

an NRTI used in covid-19

Question 13

What does the hydroxyl group on remdesivir do?

Answer 13

this is a non obligate chain terminator

although it may bond to another nucleoside, it does NOT

Question 14

What does the adenosine like moiety in remdesivir do?

Answer 14

it is involved in base paring with uracil

this is very similar to how adenosine makes base pairs, this is possibly why it gets incorporated by viral polymerase

Question 15

What is the ‘glycosidic bond’ in remdesivir?

Answer 15

normally is from ribose C to a base N

in this it is C-C and so it is more stable against nucleases as it is not a hemi-aminal bond

Question 16

What does the cyano group in remdesivir do?

Answer 16

provides less toxicity as it is not incorporated into the host polymerases

only possible by iterations and cell evaluation

Question 17

What is the phosphamide in remdesivir?

Answer 17

protide protecting group

more lipophilic than monophospate helping uptake across the cell membrane

Question 18

What does the phosphamide group on remdesivir help with?

Answer 18

activation at first and the difficult, kinase phosphorylation (first phosphate group) is already done

Question 19

What are non-nucleoside reverse transcriptase inhibitors?

Answer 19

known as allosteric inhibitors

bind to a lipophilic pocket at the base of the thumb area of the RT enzyme

Question 20

How do NNRTI’s work?

Answer 20

conformationally prevents the enzyme from allowing the single strand of RNA to be transcribed

prevents replication and protects CD4 cells

Question 21

What do 1st generation NNRTIs have?

Answer 21

butterfly wing lipo, H bond and pi pi stacking

Question 22

What do 2nd generation NNRTIs have?

Answer 22

horse shoe like shape

Question 23

What do NNRTI’s target?

Answer 23

polymerase during transcription as allosteric inhibitors

Question 24

What is made following transcription and translation?

Answer 24

large proteins

Question 25

What makes a virion?

Answer 25

when these large proteins are processed into smaller proteins

Question 26

What does protease do?

Answer 26

cleaves the larger proteins, hydrolysis of the protein peptide bond

Question 27

What is HIV protease?

Answer 27

a much smaller enzyme than the equivalent host aspartate proteases

Question 28

What does HIV protease do?

Answer 28

cleaves substrates N terminal to proline residues unlike mammalian proteases

Question 29

What is the cleave site for HIV protease?

Answer 29

Try-Pro

Question 30

What was the rationale for inhibitor design based on?

Answer 30

Phe-Pro or Tyr-Pro motif

Question 31

What do protease inhibitors do?

Answer 31

mimic the substrate with non-hydrolysable functionality

Question 32

Examples of protease inhibitors?

Answer 32

ritonavir

indinavir

saquinavir

Question 33

Drug used in the herpes simples and varicella zoster infection?

Answer 33

aciclovir

Question 34

Example of an NNRTI?

Answer 34

nevirapine