PHRM 524 Antiretroviral MedChem

How are NRTIs activated?

Must be activated to form triphosphate by host kinases

What are the two mechanisms of NRTIs?

1. Competitive inhibition of RT

2. Incorporation into DNA = chain termination (no 3' hydroxyl)

Why do NRTIs generally not inhibit DNA polymerase?

Reverse transcriptase is sloppy compared to DNA polymerase

Describe the bioavailability of NRTIs

Good oral bioavailability and BBB penetration

Which NRTI is sensitive to light and heat and why?

Zidovudine due to the azide on its structure

Be careful with storage conditions!

Where do NNRTIs bind?

To an allosteric site on the RT enzyme

What are the three important implications of allosteric binding of NNRTIs?

1. They are synergistic with NRTIs and thus typically co-dosed with them

2. They develop resistance easily

3. They are very selective for HIV-RT = no inhibition of DNA polymerase

What is a scissile bond?

A covalent chemical bond that can be broken by an enzyme

Where is the scissile bond located in HIV protease inhibitors?

In the middle of the molecule between the double bonded oxygen and the NH

What is the key to catalysis on HIV protease inhibitors?

The two aspartic acid residues present when the scissile bond is broken

What is present on the structure of protease inhibitors?

Tetrahedral mimics

What cleaves scissile bonds?

Proteases

What are the four types of proteases?

Cysteine proteases

Serine proteases

Zinc proteases

Aspartyl proteases

Describe the tetrahedral intermediate of protease inhibitors

Binds to the catalytic aspartic acid

Mimics the scissile amide bond, but isn't cleavable

What are protease inhibitors typically dosed with?

A sub-therapeutic dose of ritonavir or cobicistat which are selective CYP3A4 inhibitors

What type of enzymes can cleave DNA and RNA?

Bis-Mg enzymes

What are the acidic OH groups on integrase inhibitors present for?

Negative charge = can easily coordinate with the positively charged Mg ion

What is the importance of Mg ions coordinating with integrase inhibitors?

Important for phosphate cleavage

What is the importance of the acidic nature of the functional groups of integrase inhibitors?

Very important for metal binding

They bind Mg in their deprotonated form

What does fostemsavir bind to?

gp120