HIV

Question 1

HIV structure

Answer 1

HIV CAPSID
(INner viral protein cell )
Consists of 2 single strands of rna
Protein p24
HIV Enzymes

HIV MATRIX PROTEINS
(For integrity of the viron particle )
Protein p17 surrounds the capsid ensuring the integrity of the viron particle

VIRAL ENVELOPE
lipid bilayer
Proteins from host cell
HIV enevelope proteuns (for virus binding and fusion with host cell)
Cap- gp120
Stem - gp 41

Question 2

HIV life cycle

Question 3

What 3 types of drugs are most HIV patients treated with

Answer 3

NRTI
NNRTI
Proteas inhibitors

Question 4

Why is RT an important drug target

Answer 4

It is respisbke for converting ssRNA into viral ds DNA

responsible for activating the Ribonuckesse H enzyme which liberates pro viral DNA from RNA after transcription

Question 5

Reverse transcriptase structure

Answer 5

Heterodiameric enzyme - p66 and p51

Four subdomains of p66- palm finger thumb and connection

P66 palm domain contains polymerase active site

P51 domain contains ribonuclease h domain

Question 6

Why are RT inhibitors difficult for drug design

Answer 6

High degree of nucleotide sequence- variation between different viral strains

Question 7

NRTIs

Answer 7

Compete with nucleosides at enzyme catalytic site
Resemble the structure of nucleosides
Are prodrugs

Question 8

NNRTI

Answer 8

bind to alloesteric non substrate binding sites of enzymes
Hydrophobic
Makes the p66 domain hyper extended as it induces a rotamer conformation , changes in tyr 181 and tyr 188
Selective - 30 different classss of compound

Question 9

Examples of NRTIs

Answer 9

Didanosine
Zidovudine

Question 10

Examples of NNRTIs

Answer 10

Nervirapine
Efavirenz

Question 11

What is HIV protease

Answer 11

A proteolytic enzyme responsible for cleaving the large poly protein precursor into biologically active protein products
It hydrolysed the peptide bonds

Question 12

HIV protease structure

Answer 12

Homodimer - dimer made up of two identical protein units
Two fold rotational (c2) symmetry
2x aspartic acid residues contribute to the active catalytic site

Has a broad substrate specificity - can cleave at a variety of peptide bonds in viral polypeptides
Cleaves binds between the proline and aromatic reside . It is unusual and does not occur in mammalian proteases - selectivity over mamamilian proteases .
The synmetrical nature and its active site is not present in mammalian protease , again suggesting the possibility of drug selectivity.

Question 13

Types of HIV protease inhibitors

Answer 13

Based on transition state mimetic approach -
During cleavage of the peptide bind there would be a tetrahedral adduct - a transitional state molecule. It can mimic this and be a competitive inhibitor with the natural substance - the polypeptide

Based on distrusting the two fold rotational c2 symmetry -
By forming specific interactions with the residues involved in stabilising the dimer - dimer destabilised

Question 14

What are first generation protease inhibitors

Answer 14

Peptide inhibitors - mimic structure to peptide

Question 15

What are second generation protease inhibitors

Answer 15

Non peptide inhibitors - structure is nit similar but has ability to mimic transitional state

Question 16

Mechanism of transitional state inhibitors

Answer 16

Two aspartate residues in the enzyme active site , disposed on opposite faces of the peptide bind ti be cleaved

One asp (ASP- COO-) acts as a general base to activate the attacking water , the second asp (ASP-COOH) acts as a general acid to deprotonate the departing amine product

The two asps act in complementary fashion for breakdown of the tetrahedral adduct

Replacement of the the scissile peptide bond of the substrate with the hydroxyethylene group in the inhibitor