Header Logo

Search Result Details

Back to Search Results
This page shows the details of why an item matched the keywords from your search.
Search Results
Schiffer, Celia
One or more keywords matched the following properties of Schiffer, Celia
PropertyValue
keywords HIV
overview

Academic Background

B.A., University of Chicago, 1986
Ph.D., University of California, San Francisco, 1992

Postdoctoral Fellow, ETH-Zurich, 1992-94
Postdoctoral Fellow, Genentech, 1994-97

Interface of Evolution and Structure Based Drug Design

www.umassmed.edu/schifferlab

Constraining evolution and avoiding drug resistance

Drug resistance occurs when, through evolution, a disease no longer responds to medications. Resistance impacts the lives of millions, limiting the effectiveness of many of our most potent drugs. This often happens under the selective pressure of therapy in bacterial, viral and fungal infections and cancer due to their rapid evolution.

We combine a variety of experimental and computational techniques to understand the molecular basis of drug resistance. Our new paradigm of drug design minimizes chances of resistance. Realizing that disrupting the drug target’s activity is necessary but not sufficient for developing a robust drug that avoids resistance.

Strategies and Systems

We use multidisciplinary approaches, combining crystallography, enzymology, molecular dynamics and organic chemistry, to elucidate the molecular mechanisms of drug resistance. Resistance occurs when a heterogeneous populations of a drug target is challenged by the selective pressure of a drug. In cancer and viruses this heterogeneity is partially caused APOBEC3’s. We discovered resistance mutations occur either where drugs physically contact regions of the drug target that are not essential for substrate recognition or alter the ensemble dynamics of the drug target favoring substrate. We leverage these insights into a new strategies in structure-based drug design to minimize the likelihood for resistance by designing inhibitors to stay within the substrate envelope. This strategy not only describes most of the primary drug resistance for HIV, Hepatitis C viral protease inhibitors and influenza neuraminidase, but is generally applicable in the development of novel drugs that are less susceptible to resistance.

 
One or more keywords matched the following items that are connected to Schiffer, Celia
Item TypeName
Academic Article Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance.
Academic Article The maturation of dendritic cells results in postintegration inhibition of HIV-1 replication.
Academic Article Replacement of the P1 amino acid of human immunodeficiency virus type 1 Gag processing sites can inhibit or enhance the rate of cleavage by the viral protease.
Academic Article Cooperative fluctuations of unliganded and substrate-bound HIV-1 protease: a structure-based analysis on a variety of conformations from crystallography and molecular dynamics simulations.
Academic Article Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor.
Academic Article Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor.
Academic Article Design of HIV-1 protease inhibitors active on multidrug-resistant virus.
Academic Article Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate.
Academic Article Substrate envelope and drug resistance: crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease.
Academic Article How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease.
Academic Article Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease.
Academic Article Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis.
Academic Article Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres.
Academic Article Viral protease inhibitors.
Academic Article Additivity in the analysis and design of HIV protease inhibitors.
Academic Article Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.
Academic Article Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.
Academic Article The effect of clade-specific sequence polymorphisms on HIV-1 protease activity and inhibitor resistance pathways.
Academic Article Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones.
Academic Article Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope.
Academic Article Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes.
Academic Article Molecular Basis for Drug Resistance in HIV-1 Protease.
Academic Article First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G.
Academic Article Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.
Academic Article Context surrounding processing sites is crucial in determining cleavage rate of a subset of processing sites in HIV-1 Gag and Gag-Pro-Pol polyprotein precursors by viral protease.
Academic Article Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance.
Academic Article Extreme entropy-enthalpy compensation in a drug-resistant variant of HIV-1 protease.
Academic Article Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.
Academic Article Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease.
Academic Article Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments.
Academic Article Structure-based prediction of potential binding and nonbinding peptides to HIV-1 protease.
Academic Article Covariation of amino acid positions in HIV-1 protease.
Academic Article Combating susceptibility to drug resistance: lessons from HIV-1 protease.
Academic Article Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease.
Academic Article Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance.
Academic Article Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate.
Academic Article Substrate specificity in HIV-1 protease by a biased sequence search method.
Academic Article Role of invariant Thr80 in human immunodeficiency virus type 1 protease structure, function, and viral infectivity.
Academic Article Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands.
Academic Article N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.
Academic Article Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease.
Academic Article Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease.
Academic Article Mass spectrometry analysis of HIV-1 Vif reveals an increase in ordered structure upon oligomerization in regions necessary for viral infectivity.
Academic Article Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease.
Academic Article HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants.
Academic Article Structural analysis of human immunodeficiency virus type 1 CRF01_AE protease in complex with the substrate p1-p6.
Academic Article Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir.
Academic Article New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors.
Academic Article Human immunodeficiency virus type 1 protease-correlated cleavage site mutations enhance inhibitor resistance.
Academic Article Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance.
Academic Article Rationale for more diverse inhibitors in competition with substrates in HIV-1 protease.
Academic Article Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity.
Academic Article TMC310911, a novel human immunodeficiency virus type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors.
Academic Article Decomposing the energetic impact of drug-resistant mutations: the example of HIV-1 protease-DRV binding.
Academic Article Structural, kinetic, and thermodynamic studies of specificity designed HIV-1 protease.
Academic Article Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.
Academic Article Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50.
Academic Article Crystal structure of the DNA cytosine deaminase APOBEC3F: the catalytically active and HIV-1 Vif-binding domain.
Academic Article Interview with Celia Schiffer.
Concept HIV Antigens
Concept pol Gene Products, Human Immunodeficiency Virus
Concept HIV Long Terminal Repeat
Concept HIV-1
Concept HIV Infections
Concept HIV Protease
Concept Anti-HIV Agents
Concept HIV Integrase
Concept gag Gene Products, Human Immunodeficiency Virus
Concept HIV Antibodies
Concept HIV Protease Inhibitors
Concept vif Gene Products, Human Immunodeficiency Virus
Academic Article A sensitive assay using a native protein substrate for screening HIV-1 maturation inhibitors targeting the protease cleavage site between the matrix and capsid.
Academic Article Testing the substrate-envelope hypothesis with designed pairs of compounds.
Academic Article Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance.
Academic Article HIV-1 protease-substrate coevolution in nelfinavir resistance.
Academic Article Differential Flap Dynamics in Wild-type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation.
Academic Article Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease.
Academic Article Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease.
Academic Article Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.
Academic Article A computational analysis of the structural determinants of APOBEC3's catalytic activity and vulnerability to HIV-1 Vif.
Academic Article Development of a Novel Screening Strategy Designed to Discover a New Class of HIV Drugs.
Academic Article HIV-1 Protease and Substrate Coevolution Validates the Substrate Envelope As the Substrate Recognition Pattern.
Academic Article Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV.
Academic Article Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution.
Academic Article Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G.
Academic Article A Direct Interaction with RNA Dramatically Enhances the Catalytic Activity of the HIV-1 Protease In Vitro.
Academic Article Modulation of HIV protease flexibility by the T80N mutation.
Academic Article Improving Viral Protease Inhibitors to Counter Drug Resistance.
Academic Article Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1.
Academic Article Interdependence of Inhibitor Recognition in HIV-1 Protease.
Academic Article Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.
Academic Article Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease.
Academic Article Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance.
Academic Article HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites.
Academic Article Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA.
Academic Article Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.
Academic Article Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution.
Academic Article Correction to Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.
Academic Article NMR and MD studies combined to elucidate inhibitor and water interactions of HIV-1 protease and their modulations with resistance mutations.
Academic Article Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.
Academic Article Target-Specific Prediction of Ligand Affinity with Structure-Based Interaction Fingerprints.
Academic Article HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands To Optimize Hydrogen Bonding in the Substrate Envelope.
Academic Article Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance.
Academic Article Mechanism for APOBEC3G catalytic exclusion of RNA and non-substrate DNA.
Academic Article Characterizing Protein-Ligand Binding Using Atomistic Simulation and Machine Learning: Application to Drug Resistance in HIV-1 Protease.
Academic Article Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures.
Academic Article Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.
Academic Article Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.
Academic Article Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning.
Academic Article Analyses of HIV proteases variants at the threshold of viability reveals relationships between processing efficiency and fitness.
Academic Article HIV-1 VIF and human APOBEC3G interaction directly observed through molecular specific labeling using a new dual promotor vector.
Academic Article Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance.
Academic Article HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues.
Academic Article FcRn-enhancing mutations lead to increased and prolonged levels of the HIV CCR5-blocking monoclonal antibody leronlimab in the fetuses and newborns of pregnant rhesus macaques.
Search Criteria
  • HIV