Potential novel therapeutics targeting HIV-1 gp120: Insights into cyclotides from Clitoria ternatea

The rising threat of viral infections, especially HIV-1, has intensified efforts to discover novel antiviral strategies aimed at combating drug resistance and disrupting stages of the viral life cycle. Among natural therapeutic compounds, cyclotides have gained attention in the pharmaceutical industry owing to their structural stability, resistance to enzymatic degradation, potent antiviral activity and drug-like properties. In this study, we investigated the interaction of cyclotides from Clitoria ternatea with the HIV-1 gp120 envelope glycoprotein, a key mediator of viralhost interaction. Five cyclotides, Cliotide T18, Cter M, Cter 1, Cter 4 and Cter 33 were selected along with Kalata B1, a well-studied anti-HIV peptide, as a reference. Docking analyses showed strong binding affinities between gp120 and the cyclotides with binding energies ranging from −10.3 to −15.3 kcal/mol. Molecular dynamics simulations revealed stable interactions for Cter M, Cter 33 and Cliotide T18 based on RMSD and Rg analysis. Binding free energy calculations confirmed these findings, with Cter M showing the most favourable ΔG (−61.08 kcal/mol), comparable to Kalata B1 (−58.53 kcal/mol). These findings highlight the potential of cyclotides as scaffolds for anti-HIV therapeutics. Further research should validate efficacy, safety and clinical potential through in vitro and in vivo studies.