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One or more keywords matched the following properties of Schiffer, Celia
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keywords Drug Resistance
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 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 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 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 The challenge of developing robust drugs to overcome resistance.
Academic Article Molecular Basis for Drug Resistance in HIV-1 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 The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.
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 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 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 HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants.
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 Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.
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 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 Interview with Celia Schiffer.
Academic Article Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro.
Concept Drug Resistance, Viral
Concept Drug Resistance, Microbial
Concept Drug Resistance, Multiple
Concept Drug Resistance, Multiple, Viral
Concept Drug Resistance, Neoplasm
Concept Drug Resistance, Fungal
Academic Article Influenza virus drug resistance: a time-sampled population genetics perspective.
Academic Article Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance.
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 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 Structural analysis of asunaprevir resistance in HCV NS3/4A protease.
Academic Article A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance.
Academic Article Improving Viral Protease Inhibitors to Counter Drug Resistance.
Academic Article Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease.
Academic Article Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase.
Academic Article Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants.
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 Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease.
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 Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors.
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 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 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 Introduction: Drug Resistance.
Academic Article Deciphering Antifungal Drug Resistance in Pneumocystis jirovecii DHFR with Molecular Dynamics and Machine Learning.
Academic Article Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.
Academic Article Identification of a Permissive Secondary Mutation That Restores the Enzymatic Activity of Oseltamivir Resistance Mutation H275Y.
Academic Article Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance.
Academic Article Call for Papers: Drug Resistance in Infectious Diseases and Beyond.
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  • Drug Resistance