Journal of Medicinal Chemistry vol:56 issue:13 pages:5601-5612
HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with host proteins. We have previously identified peptide IN inhibitors derived from the alpha-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon-stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead compounds of novel HIV-1 IN inhibitors but also prototypical biochemical probes or 'nanoneedles' for the elucidation of HIV-1 IN dimerization and host co-factor interactions within their native cellular environment.