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Schiffer, Celia

One or more keywords matched the following properties of Schiffer, Celia

Property	Value
keywords	Protein Crystallography
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.

Property

Value

keywords

Protein Crystallography

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 Type	Name
Academic Article	Structural stability of disulfide mutants of basic pancreatic trypsin inhibitor: a molecular dynamics study.
Academic Article	The role of protein-solvent interactions in protein unfolding.
Academic Article	Accessibility and order of water sites in and around proteins: A crystallographic time-averaging study.
Academic Article	Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013.
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	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	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	PTEN enters the nucleus by diffusion.
Academic Article	Crystallization of human thymidylate synthase.
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	Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling.
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	Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5.
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	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	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	Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3/4A protease.
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	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	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	Methylcytosine and normal cytosine deamination by the foreign DNA restriction enzyme APOBEC3A.
Academic Article	The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.
Academic Article	Point mutants of EHEC intimin that diminish Tir recognition and actin pedestal formation highlight a putative Tir binding pocket.
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	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	Exploring the role of the solvent in the denaturation of a protein: a molecular dynamics study of the DNA binding domain of the 434 repressor.
Academic Article	Expression, purification, and characterization of thymidylate synthase from Lactococcus lactis.
Academic Article	Inclusion of solvation free energy with molecular mechanics energy: alanyl dipeptide as a test case.
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	RecA dimers serve as a functional unit for assembly of active nucleoprotein filaments.
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	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	Therapeutic targeting of C-terminal binding protein in human cancer.
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	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.
Academic Article	Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583.
Concept	Membrane Proteins
Concept	Protein Binding
Concept	Protein Transport
Concept	DNA-Binding Proteins
Concept	Protein Folding
Concept	Protein Processing, Post-Translational
Concept	Ubiquitin-Protein Ligases
Concept	Tumor Suppressor Protein p53
Concept	Seminal Plasma Proteins
Concept	Mitochondrial Proteins
Concept	Carrier Proteins
Concept	Protein Interaction Mapping
Concept	Nuclear Proteins
Concept	Recombinant Proteins
Concept	Fusion Proteins, bcr-abl
Concept	Protein Interaction Domains and Motifs
Concept	Mutant Proteins
Concept	Smad Proteins
Concept	Intracellular Signaling Peptides and Proteins
Concept	Serine Proteinase Inhibitors
Concept	Protein Denaturation
Concept	Proto-Oncogene Proteins c-mdm2
Concept	Viral Proteins
Concept	Repressor Proteins
Concept	Proteins
Concept	CREB-Binding Protein
Concept	Protein Structure, Secondary
Concept	Protein Structure, Tertiary
Concept	Adaptor Proteins, Signal Transducing
Concept	Cysteine Proteinase Inhibitors
Concept	Viral Structural Proteins
Concept	Crystallography
Concept	Protein Multimerization
Concept	Co-Repressor Proteins
Concept	Crystallography, X-Ray
Concept	Escherichia coli Proteins
Concept	Recombinant Fusion Proteins
Concept	Bacterial Outer Membrane Proteins
Concept	Viral Nonstructural Proteins
Concept	Plant Proteins
Concept	Protein Structure, Quaternary
Concept	Structural Homology, Protein
Concept	Neoplasm Proteins
Concept	Caenorhabditis elegans Proteins
Concept	Protein Conformation
Concept	Apoptosis Regulatory Proteins
Concept	Nucleocapsid Proteins
Concept	Proto-Oncogene Proteins
Concept	Proto-Oncogene Proteins c-abl
Concept	Cullin Proteins
Concept	Nerve Tissue Proteins
Concept	Protein Engineering
Academic Article	Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance.
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	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	HIV-1 protease-substrate coevolution in nelfinavir resistance.
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	Development of a Novel Screening Strategy Designed to Discover a New Class of HIV Drugs.
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	A Direct Interaction with RNA Dramatically Enhances the Catalytic Activity of the HIV-1 Protease In Vitro.
Academic Article	Structural basis for mutation-induced destabilization of profilin 1 in ALS.
Academic Article	Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy.
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 Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.
Academic Article	Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease.
Academic Article	Dengue Protease Substrate Recognition: Binding of the Prime Side.
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	Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side.
Academic Article	Interdependence of Inhibitor Recognition in HIV-1 Protease.
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	Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope.
Academic Article	Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions.
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	Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody.
Academic Article	Assembly of human C-terminal binding protein (CtBP) into tetramers.
Academic Article	Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C InfectionPublished as part of the Biochemistry series "Biochemistry to Bedside".
Academic Article	Structural Analysis of the Active Site and DNA Binding of Human Cytidine Deaminase APOBEC3B.
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	Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors.
Academic Article	APOBEC3s: DNA-editing human cytidine deaminases.
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	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	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	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	Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.
Academic Article	NAD(H) phosphates mediate tetramer assembly of human C-terminal binding protein (CtBP).
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	Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode.
Concept	Protein Domains
Concept	T-Lymphoma Invasion and Metastasis-inducing Protein 1
Academic Article	Identification of a Permissive Secondary Mutation That Restores the Enzymatic Activity of Oseltamivir Resistance Mutation H275Y.
Academic Article	Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms.
Academic Article	Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance.
Academic Article	Dual Inhibitors of Main Protease (MPro) and Cathepsin L as Potent Antivirals against SARS-CoV2.
Academic Article	Allosteric quinoxaline-based inhibitors of the flavivirus NS2B/NS3 protease.
Academic Article	Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in C.?elegans.
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	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	Direct delivery of Cas-embedded cytosine base editors as ribonucleoprotein complexes for efficient and accurate editing of clinically relevant targets.
Academic Article	Structural Analysis of Inhibitor Binding to Enterovirus-D68 3C Protease.
Academic Article	Virion-associated influenza hemagglutinin clusters upon sialic acid binding visualized by cryoelectron tomography.

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Protein
Crystallography