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Articles 31 - 34 of 34
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance, Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia Schiffer
Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance, Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia Schiffer
Celia A. Schiffer
Drug resistance is an important cause of antiretroviral therapy failure in human immunodeficiency virus (HIV)-infected patients. Mutations in the protease render the virus resistant to protease inhibitors (PIs). Gag cleavage sites also mutate, sometimes correlating with resistance mutations in the protease, but their contribution to resistance has not been systematically analyzed. The present study examines mutations in Gag cleavage sites that associate with protease mutations and the impact of these associations on drug susceptibilities. Significant associations were observed between mutations in the nucleocapsid-p1 (NC-p1) and p1-p6 cleavage sites and various PI resistance-associated mutations in the protease. Several patterns were frequently …
Three Residues In Hiv-1 Matrix Contribute To Protease Inhibitor Susceptibility And Replication Capacity, Chris Parry, Madhavi Kolli, Richard Myers, Patricia Cane, Celia Schiffer, Deenan Pillay
Three Residues In Hiv-1 Matrix Contribute To Protease Inhibitor Susceptibility And Replication Capacity, Chris Parry, Madhavi Kolli, Richard Myers, Patricia Cane, Celia Schiffer, Deenan Pillay
Celia A. Schiffer
Other than cleavage site mutations, there is little data on specific positions within Gag that impact on HIV protease inhibitor susceptibility. We have recently shown that non-cleavage site mutations in gag, particularly within matrix protein can restore replication capacity and further reduce protease inhibitor drug susceptibility when coexpressed with a drug-resistant (mutant) protease. The matrix protein of this patient-derived virus was studied in order to identify specific changes responsible for this phenotype. Three amino acid changes in matrix (R76K, Y79F, and T81A) had an impact on replication capacity as well as drug susceptibility. Introduction of these three changes into wild-type …
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Celia A. Schiffer
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high …
Structure-Based Design, Synthesis, And Structure-Activity Relationship Studies Of Hiv-1 Protease Inhibitors Incorporating Phenyloxazolidinones, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Celia Schiffer, Tariq Rana
Structure-Based Design, Synthesis, And Structure-Activity Relationship Studies Of Hiv-1 Protease Inhibitors Incorporating Phenyloxazolidinones, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Celia Schiffer, Tariq Rana
Celia A. Schiffer
A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand-enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar …