1mtb

Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy., Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA, J Virol. 2003 Jan;77(2):1306-15. PMID:12502847

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA

Categories: HIV-1 retropepsin | Human immunodeficiency virus 1 | King, N M. | Nalivaika, E A. | Prabu-Jeyabalan, M. | Schiffer, C A. | Drug resistance | Hiv-1 protease | Hydrolase-hydrolase inhibitor complex | Inhibitor binding | Substrate recognition