Molecular Basis for Reduced Cleavage Activity and Drug Resistance in D30N HIV-1 protease

Bihani, Subhash C; Hosur, Madhusoodan V

Nelfinavir is one of the FDA approved HIV-1 protease inhibitors and is a part of HAART therapy for the treatment of HIV-AIDS. Nelfinavir was the first HIV-1 protease inhibitor to be approved as a Paediatric formulation. The application of HAART had resulted into significant improvement in the life of AIDS patients. However, emergence of drug resistance in HIV-1 protease limited the use of many of these drugs including nelfinavir. A unique mutation observed frequently in patients treated with nelfinavir is D30N as it is selected exclusively by nelfinavir. It imparts very high resistance to nelfinavir but unlike other primary mutations does not give cross resistance to the majority of other drugs. D30N mutation also significantly reduces cleavage activity of HIV-1 protease and affects the viral fitness. Here, we have determined structures of D30N HIV-1 protease in unliganded form and in complex with the drug nelfinavir. These structures provide rationale for reduced cleavage activity and molecular basis of resistance induced by D30N mutation. The loss of coulombic interaction part of a crucial hydrogen bond between the drug and the enzyme, is a likely explanation for reduced affinity and drug resistance towards nelfinavir. The decreased catalytic activity of D30N HIV protease, due to altered interaction with substrates and reduced stability of folding core may be the reasons for reduced replicative capacity of the HIV harboring D30N HIV-1 protease.