BACKBONE CYCLIC PEPTIDE, WHICH MIMICS THE NUCLEAR-LOCALIZATION SIGNALOF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 MATRIX PROTEIN, INHIBITS NUCLEAR IMPORT AND VIRUS PRODUCTION IN NONDIVIDING CELLS

Here, we describe an application of the backbone cyclic (BC) proteinom imetic approach to the design and the synthesis of a BC peptide which functionally mimics the nuclear localization signal (NLS) region of th e human immunodeficiency virus type 1 matrix protein (HIV-1 MA). On th e basis of the NMR structure of HIV-1 MA, a library of BC peptides was designed and screened for the ability to inhibit nuclear import of NL S-BSA in digitonin-permeabilized HeLa and Colo-205 cultured cells. The screening yielded a lead compound (IC50 = 3 mu M) which was used for the design of a second library. This library led to the discovery of a highly potent BC peptide, designated BCvir, with an IC50 value of 35 nM. This inhibitory potency is compared to a value of 12 mu M exhibite d by the linear parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in infected nondividing cultured human T-cells and w as relatively resistant to tryptic digestion. These properties make BC vir a potential candidate for the development of a novel class of anti viral drugs which will be based on blocking nuclear import of viral ge nomes.