Covalent Trimeric Coiled Coils of the HIV gp41 HR1 Region are Extremely Potent and Broadly Neutralizing Inhibitors of Viral Infection

摘要

The key players in HIV viral entry are the envelope glycoprotein receptor-binding gpl20 and transmembrane fusogenic gp41 subunits. The mechanism of fusion involves two helical regions of gp41, an N-terminal heptad repeat (HR1) and a C-terminal heptad repeat (HR2). The HR1 and HR2 helical regions form a fusogenic structure, a six-helix-bundle, in which three alpha-helices formed by HR2 peptides pack in an antiparallel manner against a central three stranded coiled coil formed by the HR1 peptides. It is generally accepted that fusion progresses via the formation of a fusion intermediate, in which both the HR1 coiled coil and the HR2 regions are exposed. The fusion intermediate is the target of both synthetic C- and N-peptides, that inhibit viral infection by preventing formation of the 6-helix bundle. HR2 peptides are potent inhibitors of viral fusion, and the peptide DP 178 has become the first fusion inhibitor approved as a human therapeutic. Peptides from the HR1 region of gp41 protein can also inhibit viral fusion, but their potency is limited by the low tendency to form a trimeric coil-coil. Accordingly, chimeric peptides, consisting of a designed trimeric coiled coil (IZ) fused to gp41 HR1 sequences are potent inhibitors of fusion as reported for IZN17(Fig. 1).