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Full-Text Articles in Life Sciences
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Celia A. Schiffer
The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements …
Viability Of A Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights For Better Antiviral Therapy, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Viability Of A Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights For Better Antiviral Therapy, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Celia A. Schiffer
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 …
Role Of Invariant Thr80 In Human Immunodeficiency Virus Type 1 Protease Structure, Function, And Viral Infectivity, Jennifer E. Foulkes-Murzycki, Moses Prabu-Jeyabalan, Deyna Cooper, Gavin J. Henderson, Janera Harris, Ronald I. Swanstrom, Celia A. Schiffer
Role Of Invariant Thr80 In Human Immunodeficiency Virus Type 1 Protease Structure, Function, And Viral Infectivity, Jennifer E. Foulkes-Murzycki, Moses Prabu-Jeyabalan, Deyna Cooper, Gavin J. Henderson, Janera Harris, Ronald I. Swanstrom, Celia A. Schiffer
Celia A. Schiffer
Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Positions that are invariant even in the presence of drug selection define critically important residues for protease function. While the importance of conserved active-site residues is easily understood, the role of other invariant residues is not. This work focuses on invariant Thr80 at the apex of the P1 loop of HIV-1, HIV-2, and simian immunodeficiency virus protease. In a previous study, we postulated, on the basis of a molecular dynamics simulation of the unliganded protease, …