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Schiffer, Celia

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

Property	Value
keywords	Viral Proteases
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

Viral Proteases

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	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	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	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	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	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	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	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	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	Mass spectrometry analysis of HIV-1 Vif reveals an increase in ordered structure upon oligomerization in regions necessary for viral infectivity.
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	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	Genes, Viral
Concept	RNA, Viral
Concept	Antibodies, Viral
Concept	Viral Plaque Assay
Concept	Viral Proteins
Concept	DNA, Viral
Concept	Viral Structural Proteins
Concept	Antigens, Viral
Concept	Viral Nonstructural Proteins
Concept	Serine Proteases
Concept	Drug Resistance, Multiple, Viral
Concept	Peptide Hydrolases
Concept	Genome, Viral
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	The interdomain interface in bifunctional enzyme protein 3/4A (NS3/4A) regulates protease and helicase activities.
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	Structural analysis of asunaprevir resistance in HCV NS3/4A protease.
Academic Article	Investigation of protein unfolding and stability by computer simulation.
Academic Article	Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment.
Academic Article	Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy.
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	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	Dengue Protease Substrate Recognition: Binding of the Prime Side.
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	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	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	Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C InfectionPublished as part of the Biochemistry series "Biochemistry to Bedside".
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	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	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	Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses.
Academic Article	Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning.
Academic Article	Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.
Academic Article	Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies.
Academic Article	Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit.
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.
Academic Article	Viral proteases: Structure, mechanism and inhibition.
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	Analyses of HIV proteases variants at the threshold of viability reveals relationships between processing efficiency and fitness.
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	Mucosal nanobody IgA as inhalable and affordable prophylactic and therapeutic treatment against SARS-CoV-2 and emerging variants.
Academic Article	Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance.
Academic Article	Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses.
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.

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Viral
Proteases