HIV infection of human cells depends on fusion of the HIV viral membrane with the target human cell membrane. The fusion process involves multiple proteins involved in viral recognition of the human cell, with fusion mediated by the protein gp41, which undergoes a conformational change to a six-helix bundle (trimer of hairpins) that is necessary for membrane fusion to occur. It has long been recognized that preventing trimer-of-hairpins formation, via binding to the three-stranded coiled coil of gp41, can be an effective strategy in preventing HIV infection of cells. Indeed, this mechanism is the basis of effectiveness of the anti-HIV peptide drug Fuzeon. However, Fuzeon currently has limited applications due to the challenges of peptide-based drugs, including large synthetic (materials) cost of the 36 amino acid peptide and the inability to use oral delivery. These challenges could be overcome by small molecules that function equivalently to the Fuzeon protein, via disruption of the gp41 intramolecular protein-protein interactions. Herein, we will develop small molecule inhibitors of gp41 trimer-or-hairpins formation via the development of small molecule alpha-helical proteomimetics, which mimic the presentation of side chains in the hydrophobic core of gp41. These inhibitors will be examined for their ability to prevent gp41 trimer of hairpins formation, a monomeric agents and and multivalent agents. This work promised to develop novel, highly potent inhibitors of gp41 trimer-of-hairpins formation that could be extended to be novel small molecule HIV fusion inhibitors.
In the United States, 1.1 million people are infected with HIV. 50,000 new HIV infections occur per year in the US. Despite major advances in treatment of HIV infections since the emergence of HIV protease inhibitors in 1996, approximately 15,000 people per year die in the US as a result of complications from HIV infection, among the over 600,000 total Americans who have died from complications of HIV infection. For all individuals infected with HIV, the development of resistance to current treatments is a constant threat that could render these treatments ineffective. Because of the continuing development of resistance, there is a continuing need for the development of new therapeutics targeting HIV. The first stage of HIV infection involves the interaction of the HIV virus with a human cell, followed by fusion of the viral and human membranes. Blocking membrane fusion can prevent HIV infection. The HIV therapeutic Fuzeon is a large peptide which blocks HIV infection of cells via binding to the HIV protein gp41. Despite the promise of Fuzeon, it is infrequently used except in cases of resistance or cases of recent exposure, due to the large size of the peptide, the high material cost of synthesis of the peptide, and the requirement for non-oral delivery. The development of small molecule fusion inhibitors could lead to new, widely used weapons against HIV, including treatment of existing infections and prevention of new infections (prophylactic use, as in PrEP). In this proposal, we develop novel small molecule approaches to inhibition of HIV infection via the development of small molecule mimics of gp41 that can block gp41 protein-protein interactions, preventing entry of HIV into human cells.
