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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Celia A. Schiffer
Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate …
Drug Resistance Against Hcv Ns3/4a Inhibitors Is Defined By The Balance Of Substrate Recognition Versus Inhibitor Binding, Keith P. Romano, Akbar Ali, William E. Royer, Celia A. Schiffer
Drug Resistance Against Hcv Ns3/4a Inhibitors Is Defined By The Balance Of Substrate Recognition Versus Inhibitor Binding, Keith P. Romano, Akbar Ali, William E. Royer, Celia A. Schiffer
Celia A. Schiffer
Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. …
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 …
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 …