Exploring Zinc C295 as a Dual HIV-1 Integrase Inhibitor: From Strand Transfer to 3'-Processing Suppression.

Area of Science:

• Virology
• Medicinal Chemistry
• Drug Discovery

Background:

• The global AIDS pandemic necessitates innovative antiretroviral therapies (ART).
• Zinc C295 was previously identified as a potent inhibitor of HIV-1 integrase strand transfer (ST).
• This study investigates Zinc C295's potential dual-targeting capability against HIV-1 integrase 3 ac-processing (3 acP).

Purpose of the Study:

• To evaluate the dual-targeting potential of Zinc C295 against HIV-1 integrase.
• To determine Zinc C295's inhibitory activity against HIV-1 integrase 3 acP.
• To elucidate the molecular interactions underlying Zinc C295's dual inhibition mechanism.

Main Methods:

• In vitro assays adapted from ST inhibition studies were used to assess 3 acP inhibition.
• Molecular docking and molecular dynamics simulations were employed to analyze interactions with the 3 acP allosteric site.
• Computational analyses provided insights into the dual inhibitory mechanism.

Main Results:

• Zinc C295 exhibited significant inhibition of HIV-1 integrase 3 acP activity (IC50 = 4.709 ± 0.97 µM).
• Computational analyses identified key interactions within the enzyme's allosteric site.
• Evidence for a dual inhibitory mechanism against ST and 3 acP was established.

Conclusions:

• Zinc C295 demonstrates dual inhibition of HIV-1 integrase ST and 3 acP.
• This dual-action profile positions Zinc C295 as a promising candidate for next-generation ART.
• Further clinical studies are warranted to explore its therapeutic potential in managing HIV/AIDS.