Cryo-EM Structure of HIV-1 Reverse Transcriptase with N-Phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine: A New...

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Virology

Background:

• Highly Active Antiretroviral Therapy (HAART) transformed human immunodeficiency virus (HIV) from a terminal to a chronic condition.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are crucial in HAART, but drug resistance necessitates novel drug development.
• A new class of N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine HIV-1 NNRTIs has been identified.

Purpose of the Study:

• To characterize the cryo-electron microscopy (cryo-EM) structure of a novel NNRTI, compound 12126065.
• To synthesize and evaluate the activity of five analogues of this new NNRTI class.
• To assess the potential of these compounds against drug-resistant HIV-1 mutants.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of compound 12126065 at 3.53 Å resolution.
• Chemical synthesis was employed to create five analogues of the identified NNRTI class.
• Antiviral activity assays were performed, including testing against the K103N/Y181C double mutant.

Main Results:

• Compound 12126065 exhibited sub-nanomolar potency in TZM-bl cells with no observed in vivo toxicity.
• The cryo-EM structure of compound 12126065 was elucidated and compared to related NNRTIs.
• Several synthesized analogues showed promising activity, particularly against the K103N/Y181C double mutant.

Conclusions:

• The novel NNRTI class, exemplified by compound 12126065, represents a promising avenue for HIV-1 treatment.
• Structural insights from cryo-EM aid in understanding drug-target interactions.
• The activity of analogues against resistant strains provides a foundation for designing next-generation HIV-1 NNRTIs.