Design, Synthesis and Activity Evaluation of Novel Bivalent HIV-1 Fusion Inhibitor

Multivalent inhibitor is an efficient strategy for inhibitor design based on an additive effect of Delta G. In this work, we chose C34 and T20 as the template sequences to study bivalent inhibitors targeting HIV-1 gp41 NHR domain. We optimized the crosslink sites and linkers to improve anti-HIV activities of the bivalent fusion inhibitors. Compared to monovalent molecules, significant cooperative effects in the anti-cell-cell fusion activity were observed in the bivalent inhibitors, at either N- or C-terminal crosslink of both C34 and T20. beta-Alanine may be the most suitable linker for N-terminal crosslink, while C34C is the best C-terminal crosslinked molecule. Specially, the anti-HIV IC50 value of peptide BiC beta AC34 was improved from 43. 7 nmol/L to 6. 4 nmol/L, indicating the two C-peptide chains had a cooperative effect. The results show that bivalent fusion inhibitor for gp41 design could appear a cooperative effect.