Protein design of an HIV-1 entry inhibitor

Human immunodeficiency virus type-1 (HIV-1) membrane fusion is promoted by the formation of a trimer-of-hairpins structure that brings the amino- and carboxyl-terminal regions of the gp41 envelope glycoprotein ectodomain into close proximity. Peptides derived from the carboxyl-terminal region (calle d C-peptides) potently inhibit HIV-1 entry by binding to the gp41 amino-ter minal region. To test the converse of this inhibitory strategy, we designed a small protein, denoted 5-Helix, that binds the C-peptide region of gp41. The 5-Helix protein displays potent (nanomolar) inhibitory activity agains t diverse HIV-1 variants and may serve as the basis for a new class of anti viral agents. The inhibitory activity of 5-Helix also suggests a strategy f or generating an HIV-1 neutralizing antibody response that targets the carb oxyl-terminal region of the gp41 ectodomain.