The overarching goal of this Program is to determine the vulnerabilities of the HIV-1 Env protein cell entry machine as a target for disease intervention by identifying Env inhibitors, defining their structural mechanisms of action, and using a structure-mechanism framework as a guide to optimize antagonist functions. Inhibition of the initial entry of HIV-1 into host cells remains a compelling, yet elusive means to prevent infection and spread of the virus. Inhibitors of HIV-1 Env that can either block cell interactions, inactivate the trimeric virus spike protein complex before receptor encounter or disrupt receptor-induced conformational changes in the Env would hold great promise of inhibiting initial HIV-1 infection. Such inhibitors would provide virus-targeted molecular weapons both to prevent AIDS transmission, a global health priority, and to treat already-infected individuals. In spite of the great potential of Env inhibitors for AIDS intervention, structural complexity and polymorphisms of the Env proteins have presented significant challenges to progress. Nonetheless, the efforts of our Program have led to the development of two classes of Env gp120 inhibitors that utilize the highly conserved CD4 binding site, but with very different modes of action. Investigation of these inhibitors has defined unique pathways to engage the virus Env trimer and cause both inactivation of the virus and blockade of virus entry into the host cell. Our Program is ideally positioned to take advantage of these new results through state-of-the-art structure- and mechanism-based approaches, achieved by the collaborative nature of our multi-institutional research team, with strong expertise in high-resolution structure determination, structural dynamics, kinetic, thermodynamic and structural mechanisms of protein-protein interactions, chemical design and synthesis, computational methods, and virology. We will apply this team approach to structure-based design and mechanistic investigations of inhibitor chemotypes that we have already developed, and new inhibitor chemotypes as they are discovered in our own and other laboratories. Overall, the Program will provide a broad-based research infrastructure to identify new paths for the discovery of preventive and therapeutic agents that block HIV-1 Env function.
In the effort to control and ultimately eradicate the global AIDS pandemic, targeting the HIV-1 envelope (Env) remains an important means to identify preventive and therapeutic interventions. The thrust of this Program Project is to identify HIV-1 antagonists by understanding the molecular and structural mechanisms of the HIV-1 Env and the vulnerabilities of Env that can be utilized to inactivate the virus and block host cell infectin. OVERALL CRITIQUE (Chair's Summary): The overall goals of the Program Project are to identify and understand the therapeutic vulnerabilities of HIV Env and identify and optimize inhibitors that exploit these vulnerabilities. Identifying and developing small molecule antagonists targeting the Env complex for potential treatment and prevention of HIV-1 infection is highly significant. The overall program goals remain significant and compelling. HIV Env remains an attractive but underexploited antiviral drug target, particularly for microbicide development, and the combination of basic and translational research approaches being proposed represent the logical way to address this problem. There is great potential synergy from the use of highly complementary approaches in the different Projects and this is important, particularly because the problem of understanding and inhibiting different Env conformational transitions is very challenging. No single group could muster the combination of structural studies, computational analyses, thermodynamics and dynamics measurements, chemistry and virology that seem critical to success. In this regard, Dr. Chaiken's leadership is outstanding, and there are now strong and innovative procedures in place to promote the necessary synergy to ensure the full potential of the Program. Overall this is a solid highly significant program project that is likely to continue to achieve its goals and have an impact on the field of HIV drug development.
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