PHMY 624: Anti-HIV drugs

AIDS is an acquired...

immunodeficiency syndrome

What causes AIDS?

human immunodeficiency virus (HIV)

AIDS pathogenesis

-infection of host cells by virus

-helper/inducer cells

-immune cell destruction

HIV is a...

retrovirus

What does it mean to be a retrovirus?

to carry RNA, not DNA

Once HIV is inside the host cell, HIV brings...

its own enzyme

Reverse transciptase

special enzyme that converts RNA into DNA

During the HIV life cycle, _________ are used to insert viral DNA into the host's genome

integrases

HIV protease enzymes _______ long proteins into smaller, functional proteins

cut

Explain the assembly stage of the HIV life cycle?

viral RNA and proteins assemble intact virions

What is the therapeutic strategy of the HIV life cycle?

-target multiple stages of viral life cycle

-combination therapy (HAART) reduces resistance

What are the kinds of reverse transcriptase inhibitors?

-Nucleoside RT inhibitors (NRTIs)

-Tenofovir (TDF)

NRTIs are __________ analogs

thymidine

What are NRTIs converted into?

triphosphates

What is an example of NRTIs?

AZT (zidovudine)

NRTIs all lack...

3' hydroxyl groups

What are the characteristics of AZT?

-taken orally

-increases CD4 T cells

-used in combination therapy

-resistance via point mutations

Tenofovir is a ____________ prodrug

phosphate

What is tenofovir used for?

HIV and Hep B

Non-nucleoside RT inhibitors (NNRTIs) bind...

reverse transcriptase at non-substrate site

What do NNRTIs block

RNA and DNA-dependent polymerase activity

HIV protease inhibitors MOA

-cleaves viral polyproteins

-inhibitors are substrate mimics

HIV protease inhibitors contain _________________ bonds

non-cleavable

What are examples of HIV protease inhibitors

-Saquinavir

-Ritonavir

-Indinavir

-Nelfinavir

-Amprenavir

-Tipranavir

What was the first approve protease inhibitor?

Saquinavir

Saquinavir is a...

hydroxyethylamine transition state mimetic

What does Ritonavir mimic?

substrate

Ritonavir allows the protease to cleave at _________ residues

Phenylalanine

Which HIV protease inhibitor is the only one to penetrate the CNS?

Indinavir

Integrase inhibitors block integration of...

viral DNA into host genome

What are examples of integrase inhibitors?

-ralleegravir

-elvilegravir

-cabotegravir

What deoes Rallegravir inhibit?

strand-transfer reaction

Rallegravir competes with...

viral DNA

Rallegravir blocks...

integrase active site

Elivitegravir has a similar mechanism to...

rallegravir

Which integrase inhibitor is for HIV-I?

Cabotegravir

What are the 3 different entry inhibitors?

-fusion inhibitor

-CCR5 antagonist

-Capsid inhibitor

Enfuviritide is an example of a __________ inhibitor

fusion

What do fusion inhibitors, inhibit?

the fusion of HIV with cell membrane

What is an example of a CCR5 antagonist?

Maraviroc

CCR5 antagonists inhibit the binding of...

HIV to cell receptors (CCR5)

What is an example of a capsid inhibitor?

Lenacapavir

antivirals target...

virus-specific enzymes

prodrugs ____________ bioavailability

improve

combination therapy __________ resistance

lowers

HIV therapy targets...

-protease

-integrase

-entry

-reverse transcriptase

What are the prospects for anti-AIDS drugs...

-rates of new infections decreasing

-patient compliance better

-better availability

-prophylactic administration effective

reverse transcriptases bind to...

RNA template

RNA complex

degradation of RNA template of DNA

Reverse transcriptase inhibitors form...

double stranded cDNA