Designing an optimized theta-defensin peptide for HIV therapy using in-silico approaches.

The glycoproteins 41 (gp41) of human immunodeficiency virus (HIV), located on the virus's external surface, form six-helix bundles that facilitate viral entry into the host cell. Theta defensins, cyclic peptides, inhibit the formation of these bundles by binding to the GP41 CHR region. RC101, a synthetic analog of theta-defensin molecules, exhibits activity against various HIV subtypes. Molecular docking of the CHR and RC101 was done using MDockPeP and Hawdock server. The type of bonds and the essential amino acids in binding were identified using AlphaFold3, CHIMERA, RING, and CYTOSCAPE. Mutable amino acids within the peptide were determined using the CUPSAT and Duet. Thirty-two new peptides were designed, and their interaction with the CHR of the gp41 was analyzed. The physicochemical properties, toxicity, allergenicity, and antigenicity of peptides were also investigated. Most of the designed peptides exhibited higher binding affinities to the target compared to RC101; notably, peptides 1 and 4 had the highest binding affinity and demonstrated a greater percentage of interactions with critical amino acids of CHR. Peptides A and E displayed the best physiochemical properties among designed peptides. The designed peptides may present a new generation of anti-HIV drugs, which may reduce the likelihood of drug resistance.