Indoline core CD-4 mimetics are a HIV treatment that trick the virus into entering a vulnerable “open” conformation, allowing antibody-dependent cellular toxicity. Problem: HIV impacts 38 million individuals worldwide, many of whom are receiving treatment. A barrier to successful treatment is viral rebound after cessation of antiviral therapy. To infect a cell, HIV normally fuses with the target cell by using a trimeric surface glycoprotein to bind to the CD4 receptor on T cells. This binding interaction requires the surface glycoprotein to enter an “open state.” HIV hides from the body’s immune system by traveling in a protected “closed” conformation, only transitioning to a vulnerable “open” state when it is ready to infect a cell. These features make it difficult to stop viral entry, recognize the virus before it binds to a cell, and clear infected cells. Solution: Promoting this open state outside of when the virus is entering the cell allows for immune system recognition and clearance of the virus. CD-4 mimetics bind to viral surface glycoprotein, mimicking the interaction between the virus and the endogenous CD-4 receptor. This triggers a premature and stable conformational change to the open state. In this state, the virus can’t interact with a real CD-4 receptor, and thus can’t enter cells. Further, the stabilized open conformation makes the virus vulnerable to detection from the immune system. Infected cells can then be recognized by antibodies and removed by the immune system. Technology: Guided by molecular-resolution structures of a CD-4 mimetic bound to the HIV viral particle, the inventors developed improved indoline scaffold CD-4 mimetics that exploit a hydrophobic cavity in HIV glycoprotein. These improvements better stabilize the open conformation of the HIV glycoprotein, leading to a 30-fold increase in inhibition of viral entry, improved host antibody recognition, and improved removal of infected cells. Advantages:
Stage of Development:
Normalized IC50 values against viral infection for indoline CD-4 mimetic compounds compared to previous lead compound, BNM-III-170. Intellectual Property:
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Docket: 22-10040