Development of anti-HIV-1 peptides based on the concept of the discrimination of helical surfaces

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We have been confronted with epidemic threat of infectious disease caused by emerging mortal viruses including HIV-1 and SARS-CoV. A general strategy for development of anti-viral drugs targeting at a common infection machinery has been desired, which provides new methodologies for the prevention and treatment of other newly emerging viruses. Among several infection machineries, membranes fusion steps between viruses and target cells are potential targets. A wide variety of viruses are presumed to establish their cell/virus membranes fusion by formation of supramolecular structures of Env proteins of the viruses. For example, membrane fusion of HIV-1 and target cells has been well known to be mediated by formation of a six-helix bundle resulting from the coiled-coil interaction between highly α-helical N-(or heptad repeat 1:HR1) and C (or heptad repeat 2:HR2)-region in the extracellular domain of gp41 (HIV-1 Env protein). And compounds inhibiting the formation of the six-helix bundle s … More tructure in the HIV-1 infection step are well known to work as an anti-HIV-1 drug. We have remodeled the α-helical C-region (HR2)-derived peptides to develop an efficient anti-HIV-1 peptide and found that incorporation of replacement by artificial heptad sequence, X-EE-XX-KK (X=amino acid residues responsible for the interaction with N-(or HR1) region ; E=Glu ; K=Lys), into the C-region of gp41 allowed the remodeled peptides with enhanced α-helicity to exhibit high anti-HIV-1 activity. On the basis of development of this highly effective anti-HIV-1 peptide, we expected that this remodeling strategy, (referred to as X-EE-XX-KK concept), would be widely applicable to other virus using fusion machinery similar to gp41 of HIV-1. Spike (S) protein (Env protein) of SARS-CoV is supposed to be involved in the fusion process in a way to similar to gp41. We applied the same strategy using the X-EE-XX-KK concept to potential α-helical sequence (HR2 region) of the S protein, and found the designed peptides exhibit strong anti-SARS-CoV activity. Less