Synthesis of Cholesterol Conjugated Non-native Derived Heptad Repeat Sequence Peptides as Potent HIV-1 Fusion Inhibitors†

Abstract

As addition of a cholesterol group to nature peptide fusion inhibitor can dramatically increase its antiviral potency,we designed and synthesized a series of cholesterol conjugated artificial peptide with low sequence homologous from HIV-1 gp41 as HIV-1 fusion inhibitors. The cholesterol moiety was introduced into C- or N-terminal of the peptide through a thioether in cysteine side chain and a β-alanine linker to study the effect of cholesterol modification to the activity of non-natural HR sequence and explore new method to overcome the problem of HIV drug resistance. Cell-cell fusion assays showed that the fusion inhibitory activity of the C-terminal cholesterol conjugated peptide was significantly increased,while the activity of N-terminal conjugated peptide was completely lost,consistent with the reported peptide conjugation using native peptide sequence,indicated that the designed non-natural sequences had a similar mechanism of action with natural sequences. This work provided a useful base for further drug optimization and discovery of highly active nonnatural peptide sequences.