Physical Basis of the Increased Inhibition of HIV Integrase by Peptide Cyclization

HIV-1 is the (+)-strand RNA retrovirus that is responsible for the global AIDS pandemic. Like all retroviruses, it’s mode of pathogenesis relies on its ability to integrate a reversed transcribed copy of its RNA genome into the host DNA. Essential viral catalytic enzymes such as reverse transcriptase and integrase as well as endogenous cofactors are required for infection. Unfortunately, HIV-Integrase has proved to be a difficult enzyme to inhibit even when combined with highly active antiviral therapy. Therefore, targeting essential cofacters may be a viable solution to this problem. One such cofactor that is crucial for HIV infection is p75 (aka LEDGF.) In this study we examined the free energy of reorganization and the binding energy of linear and cyclic versions of a small peptide, consisting of residues from p75 that are responsible for binding HIV-IN, using temperature replica exchange simulations and Molecular Dynamics simulations employing IMPACT. Insight into the thermodynamics of this HIV-IN/p75 interaction is fundamental to the design of small drug inhibitors. A more detailed account of this study is provided in the link below.