ReaxFF-Guided Optimization of VIRIP-Based HIV-1 Entry Inhibitors.

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Virology
• Drug Discovery

Background:

• Therapeutic peptides show potential for treating viral infections but face challenges with efficacy and production costs.
• VIRIP, a peptide derived from α1-antitrypsin, inhibits HIV-1 entry by binding to the GP41 fusion peptide.
• Optimizing peptide size and activity is crucial for developing effective antiviral therapies.

Purpose of the Study:

• To optimize the size and enhance the antiviral activity of VIRIP using ReaxFF molecular dynamics simulations.
• To evaluate the contribution of individual amino acids in VIRIP's interaction with the HIV-1 GP41 fusion peptide.
• To develop a smaller, more potent, and cost-effective peptide inhibitor for HIV-1.

Main Methods:

• Utilized ReaxFF molecular dynamics (MD) simulations for in silico analysis of the VIRIP-GP41 FP complex.
• Employed NMR structure data of an optimized VIRIP derivative (VIR-165) for simulation guidance.
• Conducted HIV-1 infection assays and zebrafish toxicity studies to assess antiviral efficacy and safety.

Main Results:

• Successfully reduced the size of the HIV-1 GP41 fusion peptide inhibitor from 20 to 10 amino acids (2.28-1.11 kDa).
• The size-optimized VIRIP derivative (soVIRIP) demonstrated broad-spectrum anti-HIV-1 activity and was non-toxic in zebrafish.
• soVIRIP exhibited over 100-fold higher antiviral potency (IC50 of ~120 nM) compared to the original VIRIP, outperforming a clinically tested derivative.

Conclusions:

• ReaxFF-based MD simulations are effective for optimizing therapeutic peptide size and activity.
• The developed soVIRIP is a highly potent, non-toxic, and potentially cost-effective antiviral agent against HIV-1.
• This approach paves the way for the rational design and optimization of peptide-based therapeutics for viral diseases.