A symmetric inhibitor binds HIV-1 protease asymmetrically

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• HIV-1 protease is a key target for antiviral therapy.
• C2-symmetric inhibitors offer potential advantages in selectivity and potency.
• Understanding inhibitor-protease interactions is crucial for drug design.

Purpose of the Study:

• To synthesize and evaluate C2-symmetric monools and diols as HIV-1 protease inhibitors.
• To investigate the binding modes and potency of these inhibitors.
• To explore their inhibitory activity against other aspartic proteases.

Main Methods:

• Chemical synthesis of pseudo-C2-symmetric monools and C2-symmetric diols.
• Enzymatic assays to determine inhibition constants (Ki) against HIV-1 protease.
• X-ray crystallography to determine the structure of HIV-1 protease-inhibitor complexes.
• Molecular dynamics simulations to analyze binding stability.

Main Results:

• Diol inhibitors were 100-10,000 times more potent than analogous monools.
• Both monools and diols potently inhibited porcine pepsin, an asymmetric protease.
• X-ray crystallography revealed asymmetric binding of a symmetric diol to HIV-1 protease.
• Molecular dynamics simulations supported asymmetric binding as the more stable conformation.

Conclusions:

• C2-symmetric diols are potent HIV-1 protease inhibitors, with unexpected activity against porcine pepsin.
• The binding of symmetric inhibitors to proteases can be asymmetric, challenging traditional design principles.
• Molecular simulations and structural data provide insights into the complex interactions governing protease inhibition.