INHIBITION OF HIV TYPE-1 INFECTIVITY BY CONSTRAINED ALPHA-HELICAL PEPTIDES - IMPLICATIONS FOR THE VIRAL FUSION MECHANISM

Linear peptides derived from the membrane proximal region of the gp41 ectodomain are effective inhibitors of HIV type I (HIV-1)-mediated fus ion events. These inhibitory peptides lack structure in solution, rend ering mechanistic interpretation of their activity difficult. Using st ructurally constrained analogs of these molecules, we demonstrate that the peptides inhibit infectivity by adopting a helical conformation. Moreover, we show that a specific face of the helix must be exposed to block viral infectivity. Recent crystal structures show that the regi on of gp41 corresponding to the inhibitory peptides is helical and use s the analogous face to pack against a groove formed by an N-terminal coiled-coil trimer. Our results provide a direct link between the inhi bition of HIV-1 infectivity by these peptides and the x-ray structures , and suggest that the conformation of gp41 observed by crystallograph y represents the fusogenic state. Other agents that block HIV-1 infect ivity by binding to this groove may hold promise for the treatment of AIDS.