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Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel Caffrey, Konstantin Zeldovich, Ping Liu, Glen Gallagher, Daniel Aiello, Alyssa Porter, Evelyn Kurt-Jones, Daniel Bolon, Yu-Ping Poh, Jeffrey Jensen, Celia Schiffer, Timothy Kowalik, Robert Finberg, Jennifer Wang
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel Caffrey, Konstantin Zeldovich, Ping Liu, Glen Gallagher, Daniel Aiello, Alyssa Porter, Evelyn Kurt-Jones, Daniel Bolon, Yu-Ping Poh, Jeffrey Jensen, Celia Schiffer, Timothy Kowalik, Robert Finberg, Jennifer Wang
Glen R. Gallagher
Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Celia A. Schiffer
Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …
Substrate Envelope-Designed Potent Hiv-1 Protease Inhibitors To Avoid Drug Resistance, Madhavi Nalam, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Michael Altman, Nese Yilmaz, Bruce Tidor, Tariq Rana, Celia Schiffer
Substrate Envelope-Designed Potent Hiv-1 Protease Inhibitors To Avoid Drug Resistance, Madhavi Nalam, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Michael Altman, Nese Yilmaz, Bruce Tidor, Tariq Rana, Celia Schiffer
Celia A. Schiffer
The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed PIs share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed PIs retain robust binding to MDR protease variants and display exceptional antiviral potencies against …
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 …
Extreme Entropy-Enthalpy Compensation In A Drug-Resistant Variant Of Hiv-1 Protease, Nancy King, Moses Prabu-Jeyabalan, Rajintha Bandaranayake, Madhavi Nalam, Ellen Nalivaika, Aysegul Ozen, Turkan Haliloglu, Nese Yilmaz, Celia Schiffer
Extreme Entropy-Enthalpy Compensation In A Drug-Resistant Variant Of Hiv-1 Protease, Nancy King, Moses Prabu-Jeyabalan, Rajintha Bandaranayake, Madhavi Nalam, Ellen Nalivaika, Aysegul Ozen, Turkan Haliloglu, Nese Yilmaz, Celia Schiffer
Celia A. Schiffer
The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only. In the current study, profound changes are observed in the binding thermodynamics of a drug-resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, …
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Celia A. Schiffer
HIV-1 protease is a major drug target for AIDS therapy. With the appearance of drug-resistant HIV-1 protease variants, understanding the mechanism of drug resistance becomes critical for rational drug design. Computational methods can provide more details about inhibitor-protease binding than crystallography and isothermal titration calorimetry. The latest FDA-approved HIV-1 protease inhibitor is Darunavir (DRV). Herein, each DRV atom is evaluated by free energy component analysis for its contribution to the binding affinity with wild-type protease and ACT, a drug-resistant variant. This information can contribute to the rational design of new HIV-1 protease inhibitors.
The Molecular Basis Of Drug Resistance Against Hepatitis C Virus Ns3/4a Protease Inhibitors, Keith Romano, Akbar Ali, Cihan Aydin, Djade Soumana, Aysegul Ozen, Laura Deveau, Casey Silver, Hong Cao, Alicia Newton, Christos Petropoulos, Wei Huang, Celia Schiffer
The Molecular Basis Of Drug Resistance Against Hepatitis C Virus Ns3/4a Protease Inhibitors, Keith Romano, Akbar Ali, Cihan Aydin, Djade Soumana, Aysegul Ozen, Laura Deveau, Casey Silver, Hong Cao, Alicia Newton, Christos Petropoulos, Wei Huang, Celia Schiffer
Celia A. Schiffer
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer …
Design, Synthesis, And Biological And Structural Evaluations Of Novel Hiv-1 Protease Inhibitors To Combat Drug Resistance, Maloy Parai, David Huggins, Hong Cao, Madhavi Nalam, Akbar Ali, Celia Schiffer, Bruce Tidor, Tariq Rana
Design, Synthesis, And Biological And Structural Evaluations Of Novel Hiv-1 Protease Inhibitors To Combat Drug Resistance, Maloy Parai, David Huggins, Hong Cao, Madhavi Nalam, Akbar Ali, Celia Schiffer, Bruce Tidor, Tariq Rana
Celia A. Schiffer
A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K(i) values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C …
Molecular Basis For Drug Resistance In Hiv-1 Protease, Akbar Ali, Rajintha M. Bandaranayake, Yufeng Cai, Nancy M. King, Madhavi Kolli, Seema Mittal, Jennifer E. Foulkes-Murzycki, Madhavi N. L. Nalam, Ellen A. Nalivaika, Aysegul Ozen, Moses Prabu-Jeyabalan, Kelly Thayer, Celia A. Schiffer
Molecular Basis For Drug Resistance In Hiv-1 Protease, Akbar Ali, Rajintha M. Bandaranayake, Yufeng Cai, Nancy M. King, Madhavi Kolli, Seema Mittal, Jennifer E. Foulkes-Murzycki, Madhavi N. L. Nalam, Ellen A. Nalivaika, Aysegul Ozen, Moses Prabu-Jeyabalan, Kelly Thayer, Celia A. Schiffer
Celia A. Schiffer
HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All …
Association Of A Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23i, With Protease Inhibitor Therapy And In Vitro Drug Resistance, Elizabeth Johnston, Mark Winters, Soo-Yon Rhee, Thomas Merigan, Celia Schiffer, Robert Shafer
Association Of A Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23i, With Protease Inhibitor Therapy And In Vitro Drug Resistance, Elizabeth Johnston, Mark Winters, Soo-Yon Rhee, Thomas Merigan, Celia Schiffer, Robert Shafer
Celia A. Schiffer
We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combination with V82I, L23I was associated with a sevenfold reduction in nelfinavir susceptibility and a decrease in replication capacity. In combination with other drug resistance mutations, L23I was associated with multidrug resistance and a compensatory increase in replication capacity.
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 …
Rationale For More Diverse Inhibitors In Competition With Substrates In Hiv-1 Protease, Nevra Ozer, Celia Schiffer, Turkan Haliloglu
Rationale For More Diverse Inhibitors In Competition With Substrates In Hiv-1 Protease, Nevra Ozer, Celia Schiffer, Turkan Haliloglu
Celia A. Schiffer
The structural fluctuations of HIV-1 protease in interaction with its substrates versus inhibitors were analyzed using the anisotropic network model. The directions of fluctuations in the most cooperative functional modes differ mainly around the dynamically key regions, i.e., the hinge axes, which appear to be more flexible in substrate complexes. The flexibility of HIV-1 protease is likely optimized for the substrates' turnover, resulting in substrate complexes being dynamic. In contrast, in an inhibitor complex, the inhibitor should bind and lock down to inactivate the active site. Protease and ligands are not independent. Substrates are also more flexible than inhibitors and …
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 …
The Challenge Of Developing Robust Drugs To Overcome Resistance, Amy Anderson, Michael Pollastri, Celia Schiffer, Norton Peet
The Challenge Of Developing Robust Drugs To Overcome Resistance, Amy Anderson, Michael Pollastri, Celia Schiffer, Norton Peet
Celia A. Schiffer
Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Feature, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust drugs and the selection of resilient targets can lead to successful strategies for combating resistance.
Toward The Design Of Mutation-Resistant Enzyme Inhibitors: Further Evaluation Of The Substrate Envelope Hypothesis, Visvaldas Kairys, Michael Gilson, Viney Lather, Celia Schiffer, Miguel Fernandes
Toward The Design Of Mutation-Resistant Enzyme Inhibitors: Further Evaluation Of The Substrate Envelope Hypothesis, Visvaldas Kairys, Michael Gilson, Viney Lather, Celia Schiffer, Miguel Fernandes
Celia A. Schiffer
Previous studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study tests its applicability to several other therapeutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuraminidase. For the targets where many (> or =6) mutation data are available to compute the average mutation sensitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate envelope V(out), is found to correlate with average mutation sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold …
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate …
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, Inge Dierynck, Herwig Van Marck, Marcia Van Ginderen, Tim Jonckers, Madhavi Nalam, Celia Schiffer, Araz Raoof, Guenter Kraus, Gaston Picchio
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, Inge Dierynck, Herwig Van Marck, Marcia Van Ginderen, Tim Jonckers, Madhavi Nalam, Celia Schiffer, Araz Raoof, Guenter Kraus, Gaston Picchio
Celia A. Schiffer
TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC(50)], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC(50), >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC(50) was
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 …
Combating Susceptibility To Drug Resistance: Lessons From Hiv-1 Protease, Nancy King, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Combating Susceptibility To Drug Resistance: Lessons From Hiv-1 Protease, Nancy King, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Celia A. Schiffer
Drug resistance is a major obstacle in modern medicine. However, resistance is rarely considered in drug development and may inadvertently be facilitated, as many designed inhibitors contact residues that can mutate to confer resistance, without significantly impairing function. Contemporary drug design often ignores the detailed atomic basis for function and primarily focuses on disrupting the target's activity, which is necessary but not sufficient for developing a robust drug. In this study, we examine the impact of drug-resistant mutations in HIV-1 protease on substrate recognition and demonstrate that most primary active site mutations do not extensively contact substrates, but are critical …
Decomposing The Energetic Impact Of Drug Resistant Mutations In Hiv-1 Protease On Binding Drv, Yufeng Cai, Celia Schiffer
Decomposing The Energetic Impact Of Drug Resistant Mutations In Hiv-1 Protease On Binding Drv, Yufeng Cai, Celia Schiffer
Celia A. Schiffer
Darunavir (DRV) is a high affinity (4.5x10(-12) M, DeltaG = -15.2 kcal/mol) HIV-1 protease inhibitor. Two drug-resistant protease variants FLAP+ (L10I, G48V, I54V, V82A) and ACT (V82T, I84V) decrease the binding affinity with DRV by 1.0 kcal/mol and 1.6 kcal/mol respectively. In this study the absolute and relative binding free energies of DRV with wild-type protease, FLAP+ and ACT were calculated with MM-PB/GBSA and thermodynamic integration methods, respectively. Free energy decomposition elucidated that the mutations conferred resistance by distorting the active site of HIV-1 protease so that the residues that lost binding free energy were not limited to the sites …
Hiv-1 Protease Inhibitors From Inverse Design In The Substrate Envelope Exhibit Subnanomolar Binding To Drug-Resistant Variants, Michael Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Michael Gilson, Celia Schiffer, Tariq Rana, Bruce Tidor
Hiv-1 Protease Inhibitors From Inverse Design In The Substrate Envelope Exhibit Subnanomolar Binding To Drug-Resistant Variants, Michael Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Michael Gilson, Celia Schiffer, Tariq Rana, Bruce Tidor
Celia A. Schiffer
The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the …
The Effect Of Clade-Specific Sequence Polymorphisms On Hiv-1 Protease Activity And Inhibitor Resistance Pathways, Rajintha Bandaranayake, Madhavi Kolli, Nancy King, Ellen Nalivaika, Annie Heroux, Junko Kakizawa, Wataru Sugiura, Celia Schiffer
The Effect Of Clade-Specific Sequence Polymorphisms On Hiv-1 Protease Activity And Inhibitor Resistance Pathways, Rajintha Bandaranayake, Madhavi Kolli, Nancy King, Ellen Nalivaika, Annie Heroux, Junko Kakizawa, Wataru Sugiura, Celia Schiffer
Celia A. Schiffer
The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01_AE (AE) strain is seen principally in Southeast Asia. AE protease differs by approximately 10% in amino acid sequence from clade B protease and carries several naturally occurring polymorphisms that are associated with drug resistance in clade B. AE protease has been observed to develop resistance through a nonactive-site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active-site mutation D30N and the nonactive-site mutation N88D. Structural and biochemical studies were carried out with wild-type and NFV-resistant clade B …
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 …
Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance, Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia Schiffer
Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance, Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia Schiffer
Celia A. Schiffer
Drug resistance is an important cause of antiretroviral therapy failure in human immunodeficiency virus (HIV)-infected patients. Mutations in the protease render the virus resistant to protease inhibitors (PIs). Gag cleavage sites also mutate, sometimes correlating with resistance mutations in the protease, but their contribution to resistance has not been systematically analyzed. The present study examines mutations in Gag cleavage sites that associate with protease mutations and the impact of these associations on drug susceptibilities. Significant associations were observed between mutations in the nucleocapsid-p1 (NC-p1) and p1-p6 cleavage sites and various PI resistance-associated mutations in the protease. Several patterns were frequently …
Three Residues In Hiv-1 Matrix Contribute To Protease Inhibitor Susceptibility And Replication Capacity, Chris Parry, Madhavi Kolli, Richard Myers, Patricia Cane, Celia Schiffer, Deenan Pillay
Three Residues In Hiv-1 Matrix Contribute To Protease Inhibitor Susceptibility And Replication Capacity, Chris Parry, Madhavi Kolli, Richard Myers, Patricia Cane, Celia Schiffer, Deenan Pillay
Celia A. Schiffer
Other than cleavage site mutations, there is little data on specific positions within Gag that impact on HIV protease inhibitor susceptibility. We have recently shown that non-cleavage site mutations in gag, particularly within matrix protein can restore replication capacity and further reduce protease inhibitor drug susceptibility when coexpressed with a drug-resistant (mutant) protease. The matrix protein of this patient-derived virus was studied in order to identify specific changes responsible for this phenotype. Three amino acid changes in matrix (R76K, Y79F, and T81A) had an impact on replication capacity as well as drug susceptibility. Introduction of these three changes into wild-type …