Enhancing Protein Backbone Binding—A Fruitful Concept for Combating Drug‐Resistant HIV
Identifieur interne : 001E97 ( Main/Exploration ); précédent : 001E96; suivant : 001E98Enhancing Protein Backbone Binding—A Fruitful Concept for Combating Drug‐Resistant HIV
Auteurs : Arun K. Ghosh [États-Unis] ; David D. Anderson [États-Unis] ; Irene T. Weber [États-Unis] ; Hiroaki Mitsuya [États-Unis]Source :
- Angewandte Chemie International Edition [ 1433-7851 ] ; 2012-02-20.
English descriptors
- Teeft :
- Active site, Agents chemother, Alamo, Alamos database, Amano, Amide, Amino, Amino acid substitutions, Amino acids, Angew, Angewandte, Angewandte chemie drug design, Angewandte reviews, Antimicrob, Antiviral, Antiviral activity, Antiviral potency, Backbone, Backbone atoms, Backbone binding, Backbone conformation, Baldridge, Binding affinity, Biol, Boross, Cambridge university press, Carbonyl, Chem, Chemie, Chemother, Clinical development, Combat drug resistance, Conformation, Consensus type, Cpthf ligand, Crystal structure, Crystal structures, Crystallographic studies, Cyclic, Cyclic ether, Cyclic ether oxygen, Darunavir, Darunavir resistance, Database, Design strategy, Dimerization, Drug resistance, Drugresistance properties, Enzyme, Ether, Extensive interactions, Flaps, Functionality, Ghosh, Gmbh, Hydrogen bond, Hydrogen bonds, Hydrophobic, Hydrophobic pocket, Hydrophobic pockets, Inhibitor, Kgaa, Kovalevsky, Lett, Ligand, Macrocyclic, Macrocyclic inhibitors, Medicinal chemistry, Minimal deviation, Mitsuya, Molecular crab, Molecular insight, Mutant, Mutant proteases, Mutation, Oxygen atom, Peptide, Peptide analogue, Peptide bonds, Potency, Potent activity, Potent inhibitor, Protease, Protease backbone, Protease inhibitors, Protease mutations, Protein backbone, Protein production, Purdue university, Rapid emergence, Replication, Ring oxygen, Saquinavir, Side chain, Significant loss, Significant reduction, Strong hydrogen bond, Structural information, Subsite, Subsites, Substitution, Sulfonamide, Variant, Verlag, Verlag gmbh, Viral, Viral mutations, Viral strains, Virol, Waals interactions, Wang, Weak hydrogen bond, Weber, Weinheim, Weinheim angew, Wide spectrum, Wild type.
Abstract
The evolution of drug resistance is one of the most fundamental problems in medicine. In HIV/AIDS, the rapid emergence of drug‐resistant HIV‐1 variants is a major obstacle to current treatments. HIV‐1 protease inhibitors are essential components of present antiretroviral therapies. However, with these protease inhibitors, resistance occurs through viral mutations that alter inhibitor binding, resulting in a loss of efficacy. This loss of potency has raised serious questions with regard to effective long‐term antiretroviral therapy for HIV/AIDS. In this context, our research has focused on designing inhibitors that form extensive hydrogen‐bonding interactions with the enzyme’s backbone in the active site. In doing so, we limit the protease’s ability to acquire drug resistance as the geometry of the catalytic site must be conserved to maintain functionality. In this Review, we examine the underlying principles of enzyme structure that support our backbone‐binding concept as an effective means to combat drug resistance and highlight their application in our recent work on antiviral HIV‐1 protease inhibitors.
Impeding the evolution of drug resistance: HIV protease inhibitors are critical to antiretroviral treatment regimens. However, the rapid onset of drug resistance limits the effectiveness of most approved inhibitors. The structure‐based design of inhibitors targeting atoms in the protein backbone is an attractive strategy for maintaining drug efficacy. This approach limits the enzyme's ability to evolve resistance without sacrificing its catalytic activity.
Url:
DOI: 10.1002/anie.201102762
Affiliations:
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In HIV/AIDS, the rapid emergence of drug‐resistant HIV‐1 variants is a major obstacle to current treatments. HIV‐1 protease inhibitors are essential components of present antiretroviral therapies. However, with these protease inhibitors, resistance occurs through viral mutations that alter inhibitor binding, resulting in a loss of efficacy. This loss of potency has raised serious questions with regard to effective long‐term antiretroviral therapy for HIV/AIDS. In this context, our research has focused on designing inhibitors that form extensive hydrogen‐bonding interactions with the enzyme’s backbone in the active site. In doing so, we limit the protease’s ability to acquire drug resistance as the geometry of the catalytic site must be conserved to maintain functionality. In this Review, we examine the underlying principles of enzyme structure that support our backbone‐binding concept as an effective means to combat drug resistance and highlight their application in our recent work on antiviral HIV‐1 protease inhibitors.</div><div type="abstract" xml:lang="en">Impeding the evolution of drug resistance: HIV protease inhibitors are critical to antiretroviral treatment regimens. However, the rapid onset of drug resistance limits the effectiveness of most approved inhibitors. The structure‐based design of inhibitors targeting atoms in the protein backbone is an attractive strategy for maintaining drug efficacy. This approach limits the enzyme's ability to evolve resistance without sacrificing its catalytic activity.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li><li>Indiana</li><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Indiana"><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name></region><name sortKey="Anderson, David D" sort="Anderson, David D" uniqKey="Anderson D" first="David D." last="Anderson">David D. Anderson</name><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name><name sortKey="Mitsuya, Hiroaki" sort="Mitsuya, Hiroaki" uniqKey="Mitsuya H" first="Hiroaki" last="Mitsuya">Hiroaki Mitsuya</name><name sortKey="Weber, Irene T" sort="Weber, Irene T" uniqKey="Weber I" first="Irene T." last="Weber">Irene T. Weber</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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