Long-Acting BMS-378806 Analogues Stabilize the State-1 Conformation of the Human Immunodeficiency Virus Type 1 Envelope Glycoproteins
Shitao Zou, Shijian Zhang, Althea Gaffney, Haitao Ding, Maolin Lu, Jonathan R. Grover, Mark P. Farrell, Hanh T. Nguyen, Connie Zhao, Saumya Anang, Meiqing Zhao, Mohammadjavad Mohammadi, Scott C. Blanchard, Cameron F. Abrams, Navid Madani, Walther Mothes, John C. Kappes, Amos B. Smith, Joseph Sodroski
Abstract
The envelope glycoprotein (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) mediates the entry of the virus into host cells and is also the target for antibodies. During virus entry, Env needs to change shape. Env flexibility also contributes to the ability of HIV-1 to evade the host immune response; many shapes of Env raise antibodies that cannot recognize the functional Env and therefore do not block virus infection. We found that an HIV-1 entry inhibitor, BMS-806, stabilizes the functional shape of Env. We developed new variants of BMS-806 that stabilize Env in its natural state for long periods of time. The availability of such long-acting stabilizers of Env shape will allow the natural Env conformation to be characterized and tested for efficacy as a vaccine.