Currently, therapeutic management of HIV infection and pathogenesis is generally based upon administration of combination therapy with multiple inhibitors of the HIV type 1 (HIV-1) reverse transcriptase and protease. Although this approach has resulted in significant suppression of viral loads in a substantial number of patients, the long-term treatment outlook is negatively impacted by a variety of issues including a high rate of drug protocol violations, drug toxicity, and the persistence of latent reservoirs of virus in long-lived populations of infected cells. Additionally, the extreme mutability of the virus, and the fact that fairly significant changes in the structures of key viral enzymes do not always translate into gross inefficiencies in their respective functions, renders combination therapy with a particular drug protocol eventually ineffectual in most cases.
These considerations imply that an appropriate target against which to develop anti-HIV, and by extension, other antiretroviral therapies, is a mutationally intolerant protein that plays essential and diverse roles in various phases of the viral replication cycle. A heretofore unexploited target that fits this general profile is the nucleocapsid protein of HIV-1. This small, very basic and highly conserved protein participates in numerous obligate stages of the viral replication cycle, and mutations in its primary structure have been observed to result in the production of non-infectious virions. By studying the structure of the nucleocapsid protein when it is bound to other viral molecular components, we have devised a plan to mimic these components with small organic molecules. These molecules may ultimately serve as lead drug compounds.
To aid in the design of the small molecule nucleocapsid protein inhibitors, we have been using a number of computational methods and molecular modeling programs-with each enabling us to add additional layers of refinement to our lead compound structures. As a consequence, we have made significant progress in the design of small molecule inhibitors, and this has enabled us to advance to the stage where the compounds are being synthesized in the laboratory. Completion of the syntheses will allow us to test our ‘first generation’ inhibitors, whose structures we will further refine as the results of their ability to inhibit nucleocapsid protein functions are acquired.