| Description |
Thirty four million people are infected with HIV, the causative agent of acquired immunodeficiency syndrome (AIDS), which has caused an estimated 25 million deaths in the three decades since the virus was identified. Dramatic progress has been made in understanding the viral lifecycle, enabling the development of safe and effective antiretroviral therapies that greatly reduce AIDS-associated mortality. Viral entry is mediated by the viral glycoprotein, Env. Env, composed of gp120 and gp41 subunits, adopts a transient conformation known as the prehairpin intermediate during fusion that is vulnerable to inhibition by peptides that bind the gp41 N-trimer region. Our lab has developed D-peptide inhibitors that bind to the N-trimer and prevent viral entry. The HIV lifecycle, current therapeutics, and emerging fields of HIV prevention and treatment are described in Chapter 1. Chapter 2 describes the discovery of highly potent D-peptide inhibitors of entry that bind to the N-trimer region and inhibit viral entry. These peptides, optimized by structure-guided mirror-image phage display, inhibit viral entry with nM potency. Trimerization of D-peptide inhibitors yields significant further improvement in potency due to avidity, and inhibit a broad panel of primary isolates. D-peptides are insensitive to proteolysis, a significant advantage over L-peptide inhibitors of entry. |
