Designing drugs against heterogeneous targets

Freire, Ernesto

doi:10.1038/nbt0102-15

Cited by 38 publications

(37 citation statements)

References 10 publications

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“…Analysis of protease mutations associated with drug resistance is also confounded by the existence of many viral subtypes carrying naturally occurring polymorphisms [9]. The genomic differences among HIV-1 proteases can be as high as 30% and range from 10%-70% within the retroviral protease class [3]. Mutations contributing to viral resistance to antiviral drugs in one particular HIV subtype are found frequently in equivalent positions in the genes of other HIV subtypes or other retroviral proteases [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

A Look inside HIV Resistance through Retroviral Protease Interaction Maps

Kontijevskis¹,

Prūsis²,

Petrovska³

et al. 2005

PLoS Comput Biol

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Retroviruses affect a large number of species, from fish and birds to mammals and humans, with global socioeconomic negative impacts. Here the authors report and experimentally validate a novel approach for the analysis of the molecular networks that are involved in the recognition of substrates by retroviral proteases. Using multivariate analysis of the sequence-based physiochemical descriptions of 61 retroviral proteases comprising wild-type proteases, natural mutants, and drug-resistant forms of proteases from nine different viral species in relation to their ability to cleave 299 substrates, the authors mapped the physicochemical properties and cross-dependencies of the amino acids of the proteases and their substrates, which revealed a complex molecular interaction network of substrate recognition and cleavage. The approach allowed a detailed analysis of the molecular-chemical mechanisms involved in substrate cleavage by retroviral proteases.Citation: Kontijevskis A, Prusis P, Petrovska R, Yahorava S, Mutulis F, et al. (2007) A look inside HIV resistance through retroviral protease interaction maps. PLoS Comput Biol 3(3): e48.

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Section: Introductionmentioning

confidence: 99%

A Look inside HIV Resistance through Retroviral Protease Interaction Maps

Kontijevskis¹,

Prūsis²,

Petrovska³

et al. 2005

PLoS Comput Biol

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“…Similarly, codon usage within the influenza hemagglutinin protein seems to be biased to favor more rapid antigenic drift (14). Furthermore, in HIV-1 protease, the probability of mutation is not randomly distributed within the structure but rather concentrated at sites that alter the geometry of the protein-binding domain, conferring significant propensity for antigenic drift (18). Such behavior is not mere curiosity and has widespread implications for drug design and the evolution of drug resistance (19).…”

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confidence: 99%

Evolvability is a selectable trait

Earl

Deem

2004

Proc. Natl. Acad. Sci. U.S.A.

202

165

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Concomitant with the evolution of biological diversity must have been the evolution of mechanisms that facilitate evolution, because of the essentially infinite complexity of protein sequence space. We describe how evolvability can be an object of Darwinian selection, emphasizing the collective nature of the process. We quantify our theory with computer simulations of protein evolution. These simulations demonstrate that rapid or dramatic environmental change leads to selection for greater evolvability. The selective pressure for large-scale genetic moves such as DNA exchange becomes increasingly strong as the environmental conditions become more uncertain. Our results demonstrate that evolvability is a selectable trait and allow for the explanation of a large body of experimental results.Darwin was obsessed with variation. His books, considered as an ensemble, devote much more attention to variation than to natural selection, because he knew that no satisfactory theory of evolutionary change could be constructed until the causes of variation and the empirical rule of its form and amount had been elucidated (1).

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“…For HIV protease in fact, the probability for a given residue to undergo mutation is not randomly distributed within the protein structure. 58 Designing against a movable target is particularly challenging, but at the same time it offers many more opportunities. Our combinatorial experiments on the HCV protease demonstrate that a large enzyme conformational ensemble can be matched by a correspondingly large set of peptide inhibitors, each one stabilizing a given conformer.…”

Section: Peptide Combinatorial Libraries: a Shotgun Approach To Enzymmentioning

confidence: 99%

Inhibiting viral proteases: Challenges and opportunities

Bianchi

Pessi

2002

Biopolymers

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Inhibitor design against viral targets must take into account the peculiar characteristics of viral biology-in particular, the plasticity of their replicative machinery. This includes maturational cleavage of the polyprotein, which is mediated by virally encoded proteases. Designing against a movable target is particularly challenging, but at the same time it offers new opportunities. Here we describe our experience with the NS3/4A (NS: nonstructural) serine protease of human hepatitis C virus (HCV). By extensive use of combinatorial peptide libraries, various inhibitor types were generated, including product inhibitors, serine traps, P-P' inhibitors, and prime side inhibitors. The latter represent a first case for a serine protease. A key finding, derived from structural studies utilizing these inhibitors, was that NS3 is an induced-fit protease, requiring both the NS4A cofactor protein and the substrate to fully activate its catalytic machinery. In the absence of cofactor and/or substrate, NS3 exists in solution as a large conformational ensemble, which can be matched by a correspondingly large set of peptide inhibitors, each one stabilizing a given conformer. In the perspective of inhibiting viral proteases in general, we suggest that combinatorial ligand ensembles may be a powerful tool, to contrast the adaptive potential of the viral quasispecies.

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Designing drugs against heterogeneous targets

Cited by 38 publications

References 10 publications

A Look inside HIV Resistance through Retroviral Protease Interaction Maps

A Look inside HIV Resistance through Retroviral Protease Interaction Maps

Evolvability is a selectable trait

Inhibiting viral proteases: Challenges and opportunities

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