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One or more keywords matched the following properties of Schiffer, Celia
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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 Structural stability of disulfide mutants of basic pancreatic trypsin inhibitor: a molecular dynamics study.
Academic Article Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor.
Academic Article PTEN enters the nucleus by diffusion.
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 Contribution of Ser386 and Ser396 to activation of interferon regulatory factor 3.
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 Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.
Academic Article Extreme entropy-enthalpy compensation in a drug-resistant variant of HIV-1 protease.
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 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 Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands.
Academic Article Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease.
Academic Article Prediction of homologous protein structures based on conformational searches and energetics.
Academic Article Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease.
Academic Article Human immunodeficiency virus type 1 protease-correlated cleavage site mutations enhance inhibitor resistance.
Academic Article Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.
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 Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro.
Academic Article Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia.
Concept Mutation
Concept Point Mutation
Concept Mutation, Missense
Academic Article Influenza virus drug resistance: a time-sampled population genetics perspective.
Academic Article Testing the substrate-envelope hypothesis with designed pairs of compounds.
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 Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV.
Academic Article The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization.
Academic Article Structural basis for mutation-induced destabilization of profilin 1 in ALS.
Academic Article Modulation of HIV protease flexibility by the T80N mutation.
Academic Article A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance.
Academic Article Structural and molecular analysis of a protective epitope of Lyme disease antigen OspA and antibody interactions.
Academic Article CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.
Academic Article Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.
Academic Article Synonymous Mutations at the Beginning of the Influenza A Virus Hemagglutinin Gene Impact Experimental Fitness.
Academic Article Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions.
Academic Article Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A 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 Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody.
Academic Article A call to arms: Unifying the fight against resistance.
Academic Article Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia.
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 Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance.
Academic Article Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir.
Academic Article Characterizing Protein-Ligand Binding Using Atomistic Simulation and Machine Learning: Application to Drug Resistance in HIV-1 Protease.
Academic Article Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors.
Academic Article Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes.
Academic Article A cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction.
Academic Article Crystal Structure of a Soluble APOBEC3G Variant Suggests ssDNA to Bind in a Channel that Extends between the Two Domains.
Academic Article Cryo-EM structure of CtBP2 confirms tetrameric architecture.
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 Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies.
Academic Article Structural basis of substrate specificity in human cytidine deaminase family APOBEC3s.
Academic Article Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations.
Concept Silent Mutation
Academic Article Identification of a Permissive Secondary Mutation That Restores the Enzymatic Activity of Oseltamivir Resistance Mutation H275Y.
Academic Article Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance.
Academic Article Contributions of Hyperactive Mutations in Mpro from SARS-CoV-2 to Drug Resistance.
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  • Mutation