Identification of a beta3-peptide HIV fusion inhibitor with improved potency in live cells

Abstract

We recently reported a beta(3)-decapeptide, betaWWI-1, that binds a validated gp41 model in vitro and inhibits gp41-mediated fusion in cell culture. Here we report six analogs of betaWWI-1 containing a variety of non-natural side chains in place of the central tryptophan of the WWI-epitope. These analogs were compared on the basis of both gp41 affinity in vitro and fusion inibition in live, HIV-infected cells. One new beta(3)-peptide, betaWXI-a, offers a significantly improved CC(50)/EC(50) ratio in the live cell assay.

Figure 1

Helical net representations of βWWI-1 and βWXI-a—f. β-homoamino acids are identified by the single letter code used for the corresponding α-amino acid. O represents ornithine.

Figure 2

Plots illustrating survival of HIV-infected MT-2 cells in the presence of the indicated β-peptide. EC₅₀ values reported represent the β-peptide concentration required to achieve 50% survival of infected cells; CC₅₀ values represent the concentration required to achieve 50% survival of uninfected cells. Viability was measured with an MTT colorimetric assay, as described in the text.

Figure 3

Models representing the interface between the N-peptide surface pocket (grey) and the central epitope residue of βWWI-1, βWXI-a and βWXI-b. Models were constructed using the programs Spartan (Wavefunction, Inc.) and PyMOL (DeLano Scientific, LLC) and the high-resolution structure 1gzl of the α-peptide C14linkmid bound to IQN17.