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Interview With Celia Schiffer, Celia Schiffer
Interview With Celia Schiffer, Celia Schiffer
Celia A. Schiffer
Celia Schiffer, a Professor in Biochemistry and Molecular Pharmacology; a former Director of UMass Center for AIDS Research; and a Founder and Co-Director for the Institute for Drug Resistance (University of Massachusetts Medical School, MA, USA). Schiffer has an undergraduate degree in physics from the University of Chicago, with a PhD in biophysics from University of California, San Francisco (CA, USA). She was a postdoctoral associate first at the ETH in Zurich and then at Genentech in San Francisco. Schiffer has published more than 100 peer reviewed journal articles. Her laboratory primarily uses structural biology, biophysical and chemistry techniques to …
Cooperative Effects Of Drug-Resistance Mutations In The Flap Region Of Hiv-1 Protease, Jennifer Foulkes-Murzycki, Christina Rosi, Nese Yilmaz, Robert Shafer, Celia Schiffer
Cooperative Effects Of Drug-Resistance Mutations In The Flap Region Of Hiv-1 Protease, Jennifer Foulkes-Murzycki, Christina Rosi, Nese Yilmaz, Robert Shafer, Celia Schiffer
Celia A. Schiffer
Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites …
Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer
Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer
Celia A. Schiffer
Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, …
Co-Evolution Of Nelfinavir-Resistant Hiv-1 Protease And The P1-P6 Substrate, Madhavi Kolli, Stephane Lastere, Celia Schiffer
Co-Evolution Of Nelfinavir-Resistant Hiv-1 Protease And The P1-P6 Substrate, Madhavi Kolli, Stephane Lastere, Celia Schiffer
Celia A. Schiffer
The selective pressure of the competitive protease inhibitors causes both HIV-1 protease and occasionally its substrates to evolve drug resistance. We hypothesize that this occurs particularly in substrates that protrude beyond the substrate envelope and contact residues that mutate in response to a particular protease inhibitor. To validate this hypothesis, we analyzed substrate and protease sequences for covariation. Using the chi2 test, we show a positive correlation between the nelfinavir-resistant D30N/N88D protease mutations and mutations at the p1-p6 cleavage site as compared to the other cleavage sites. Both nelfinavir and the substrate p1-p6 protrude beyond the substrate envelope and contact …
Crystal Structure Of Lysine Sulfonamide Inhibitor Reveals The Displacement Of The Conserved Flap Water Molecule In Human Immunodeficiency Virus Type 1 Protease, Madhavi Nalam, Anik Peeters, Tim Jonckers, Inge Dierynck, Celia Schiffer
Crystal Structure Of Lysine Sulfonamide Inhibitor Reveals The Displacement Of The Conserved Flap Water Molecule In Human Immunodeficiency Virus Type 1 Protease, Madhavi Nalam, Anik Peeters, Tim Jonckers, Inge Dierynck, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that bind to the protease in a novel fashion. Most of the inhibitors that are on the market are peptidomimetics, where a conserved water molecule mediates hydrogen bonding interactions between the inhibitors and the flaps of the protease. Recently a new class of inhibitors, lysine sulfonamides, was developed to combat the resistant variants of HIV protease. Here we report the crystal structure of a lysine sulfonamide. This inhibitor binds to the active site …
Structural Basis For Coevolution Of A Human Immunodeficiency Virus Type 1 Nucleocapsid-P1 Cleavage Site With A V82a Drug-Resistant Mutation In Viral Protease, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Structural Basis For Coevolution Of A Human Immunodeficiency Virus Type 1 Nucleocapsid-P1 Cleavage Site With A V82a Drug-Resistant Mutation In Viral Protease, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Celia A. Schiffer
Maturation of human immunodeficiency virus (HIV) depends on the processing of Gag and Pol polyproteins by the viral protease, making this enzyme a prime target for anti-HIV therapy. Among the protease substrates, the nucleocapsid-p1 (NC-p1) sequence is the least homologous, and its cleavage is the rate-determining step in viral maturation. In the other substrates of HIV-1 protease, P1 is usually either a hydrophobic or an aromatic residue, and P2 is usually a branched residue. NC-p1, however, contains Asn at P1 and Ala at P2. In response to the V82A drug-resistant protease mutation, the P2 alanine of NC-p1 mutates to valine …
Mechanism Of Substrate Recognition By Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed By A Novel Structural Intermediate, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Keith Romano, Celia A. Schiffer
Mechanism Of Substrate Recognition By Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed By A Novel Structural Intermediate, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Keith Romano, Celia A. Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual "intermediate" conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer …
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Celia A. Schiffer
The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements …
Hydrophobic Sliding: A Possible Mechanism For Drug Resistance In Human Immunodeficiency Virus Type 1 Protease, Jennifer Foulkes-Murzycki, Walter Scott, Celia Schiffer
Hydrophobic Sliding: A Possible Mechanism For Drug Resistance In Human Immunodeficiency Virus Type 1 Protease, Jennifer Foulkes-Murzycki, Walter Scott, Celia Schiffer
Celia A. Schiffer
Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resistance is not understood. From analysis of molecular dynamics simulations, 19 core hydrophobic residues appear to facilitate the conformational changes that occur in HIV-1 protease. The hydrophobic core residues slide by each other, exchanging one hydrophobic van der Waal contact for another, with little energy penalty, while maintaining many structurally important hydrogen bonds. Such hydrophobic sliding may represent a general mechanism by which proteins undergo conformational changes. Mutation of these residues in HIV-1 protease …
Viability Of A Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights For Better Antiviral Therapy, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Viability Of A Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights For Better Antiviral Therapy, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Celia A. Schiffer
Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more …
Role Of Invariant Thr80 In Human Immunodeficiency Virus Type 1 Protease Structure, Function, And Viral Infectivity, Jennifer E. Foulkes-Murzycki, Moses Prabu-Jeyabalan, Deyna Cooper, Gavin J. Henderson, Janera Harris, Ronald I. Swanstrom, Celia A. Schiffer
Role Of Invariant Thr80 In Human Immunodeficiency Virus Type 1 Protease Structure, Function, And Viral Infectivity, Jennifer E. Foulkes-Murzycki, Moses Prabu-Jeyabalan, Deyna Cooper, Gavin J. Henderson, Janera Harris, Ronald I. Swanstrom, Celia A. Schiffer
Celia A. Schiffer
Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Positions that are invariant even in the presence of drug selection define critically important residues for protease function. While the importance of conserved active-site residues is easily understood, the role of other invariant residues is not. This work focuses on invariant Thr80 at the apex of the P1 loop of HIV-1, HIV-2, and simian immunodeficiency virus protease. In a previous study, we postulated, on the basis of a molecular dynamics simulation of the unliganded protease, …