Header Logo

Search Result Details

This page shows the details of why an item matched the keywords from your search.
One or more keywords matched the following properties of Schiffer, Celia
PropertyValue
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 Structural stability of disulfide mutants of basic pancreatic trypsin inhibitor: a molecular dynamics study.
Academic Article Accessibility and order of water sites in and around proteins: A crystallographic time-averaging study.
Academic Article Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site.
Academic Article Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance.
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 Substrate envelope and drug resistance: crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease.
Academic Article Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling.
Academic Article Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres.
Academic Article Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5.
Academic Article Additivity in the analysis and design of HIV protease inhibitors.
Academic Article Crystal structure of the APOBEC3G catalytic domain reveals potential oligomerization interfaces.
Academic Article Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.
Academic Article Structure of a phage display-derived variant of human growth hormone complexed to two copies of the extracellular domain of its receptor: evidence for strong structural coupling between receptor binding sites.
Academic Article Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones.
Academic Article Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes.
Academic Article First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G.
Academic Article Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance.
Academic Article The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.
Academic Article Nitric oxide-mediated inhibition of Hdm2-p53 binding.
Academic Article Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.
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 Promise of advances in simulation methods for protein crystallography: implicit solvent models, time-averaging refinement, and quantum mechanical modeling.
Academic Article Simultaneous refinement of the structure of BPTI against NMR data measured in solution and X-ray diffraction data measured in single crystals.
Academic Article Accounting for molecular mobility in structure determination based on nuclear magnetic resonance spectroscopic and X-ray diffraction data.
Academic Article Expression, purification, and characterization of thymidylate synthase from Lactococcus lactis.
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 Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate.
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 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 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 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 Quantitative comparison of errors in 15N transverse relaxation rates measured using various CPMG phasing schemes.
Academic Article Structural, kinetic, and thermodynamic studies of specificity designed HIV-1 protease.
Academic Article Mass spectrometry tools for analysis of intermolecular interactions.
Academic Article Structural insights into neuronal K+ channel-calmodulin complexes.
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.
Concept Nuclear Magnetic Resonance, Biomolecular
Concept Quantitative Structure-Activity Relationship
Concept Nuclear Proteins
Concept Molecular Structure
Concept Protein Structure, Secondary
Concept Protein Structure, Tertiary
Concept Viral Structural Proteins
Concept Protein Structure, Quaternary
Concept Structural Homology, Protein
Concept Structure-Activity Relationship
Concept Receptors, Cytoplasmic and Nuclear
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 The interdomain interface in bifunctional enzyme protein 3/4A (NS3/4A) regulates protease and helicase activities.
Academic Article Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design.
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 Structural analysis of asunaprevir resistance in HCV NS3/4A protease.
Academic Article A novel Geobacteraceae-specific outer membrane protein J (OmpJ) is essential for electron transport to Fe(III) and Mn(IV) oxides in Geobacter sulfurreducens.
Academic Article Investigation of protein unfolding and stability by computer simulation.
Academic Article The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization.
Academic Article Structure-guided design of a high affinity inhibitor to human CtBP.
Academic Article REdiii: a pipeline for automated structure solution.
Academic Article Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G.
Academic Article Structural basis for mutation-induced destabilization of profilin 1 in ALS.
Academic Article Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.
Academic Article Structural and molecular analysis of a protective epitope of Lyme disease antigen OspA and antibody interactions.
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 Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope.
Academic Article Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease.
Academic Article Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity.
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 Structural Analysis of the Active Site and DNA Binding of Human Cytidine Deaminase APOBEC3B.
Academic Article Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA.
Academic Article Citrullination of NF-?B p65 promotes its nuclear localization and TLR-induced expression of IL-1? and TNFa.
Academic Article Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.
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 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 and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir.
Academic Article Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures.
Academic Article Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors.
Academic Article Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.
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 Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses.
Academic Article Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.
Academic Article Inhibiting HTLV-1 Protease: A Viable Antiviral Target.
Academic Article Introduction: Drug Resistance.
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.
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 Viral proteases: Structure, mechanism and inhibition.
Academic Article Quantitative structural analysis of influenza virus by cryo-electron tomography and convolutional neural networks.
Academic Article Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state.
Academic Article Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in C.?elegans.
Academic Article Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses.
Academic Article Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.
Academic Article Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.
Academic Article Structural Analysis of Inhibitor Binding to Enterovirus-D68 3C Protease.
Search Criteria
  • Nuclear
  • Structure