Substrate Envelope and Drug Resistance: Crystal Structure of RO1 in Complex with Wild-Type Human Immunodeficiency Virus Type 1 Protease

Prabu-Jeyabalan, M.; King, Nancy M. P.; Nalivaika, E.A.; Heilek-Snyder, Gabrielle; Cammack, Nick; Schiffer, Celia A.

doi:10.1128/aac.50.4.1518-1521.2006

Cited by 34 publications

(31 citation statements)

References 18 publications

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“…Structure-based design strategies can utilize this model as an added constraint to develop inhibitors that fit within the substrate envelope. In fact, previous work in our laboratory provides proof-of-concept for the successful incorporation of the substrate envelope in the design of unique HIV protease inhibitors, which maintain high affinities against a panel of multidrug resistant variants of HIV-1 protease (42,(48)(49)(50)(51)(52)(53). As a general paradigm, design efforts incorporating the substrate envelope would facilitate a more rationale evaluation of drug candidates and lead to the development of more robust inhibitors that are less susceptible to resistance.…”

Section: Discussionmentioning

confidence: 99%

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

Romano

Ali

Royer

et al. 2010

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

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Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates.drug design | hepatitis C | substrate envelope D rug resistance is a major obstacle in the treatment of quickly evolving diseases. Hepatitis C virus (HCV) is a genetically diverse Hepacivirus of the Flaviviridae family infecting an estimated 180 million people worldwide (1). The viral RNA genome is translated as a single polyprotein and subsequently processed by host-cell and viral proteases into structural (C, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins (2). The viral RNA-dependent RNA polymerase, NS5B, is inherently inaccurate and misincorporation of bases accounts for a very high mutation rate (3). While some mutations are neutral, others will alter the viability of the virus and propagate with varying efficiencies in each patient. Thus HCV infected individuals will develop a heterogeneous population of virus variants known as quasispecies (4). As patients begin treatment, the selective pressures of antiviral drugs will favor drug resistant variants (5). Therefore, an inhibitor must not only recognize one protein variant, but an ensemble of related enzymes. A detailed understanding of the atomic mechanisms of resistance is essential to effectively combat drug resistance against HCV antivirals.The essential HCV NS3/4A protease is an attractive therapeutic target responsible for cleaving at least four sites along the viral polyprotein. These sites share little sequence homology except for an acid at position P6, Cys or Thr at P1, and Ser or Ala at P1′ (Table S1). The first cleavage event at the 3-4A junction occurs in cis as a unimolecular process, while the remaining substrates are processed bimolecularly in trans. The NS3/4A protease also cleaves the human cellular targets TRIF and MAVS, which confounds the innate immune response to viral infection (6-8).Early drug design efforts were hampered by the relatively shallow, featureless architecture of the protease active site. The eventual observation of N-terminal product inhibition served as a stepping stone f...

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Section: Discussionmentioning

confidence: 99%

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

Romano

Ali

Royer

et al. 2010

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

Self Cite

182

245

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“…Many of these mutations are associated with multi-drug resistance. The extent to which a given inhibitor fits within the envelope can be used to predict the extent to which inhibitors will likely be susceptible to resistance [40,41]. Reinforcing the conclusion that drug resistance occurs at residues that are more important for inhibitor binding than for substrate recognition, as mutation of them adversely impacts inhibitor binding with minimal effect on substrate processing.…”

Section: Substrate Recognition and Drug Resistancementioning

confidence: 99%

New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors

Nalam

Schiffer

2008

Current Opinion in HIV and AIDS

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Purpose of review-Drug resistance occurs as a result when the balance between the binding of inhibitors and the turnover of substrates is perturbed in favor of the substrates. Resistance is quite wide spread to the HIV-1 protease inhibitors permitting the protease to process its ten different substrates. This processing of the substrates permits the HIV-1 virus to mature and become infectious. Designing HIV-1 protease inhibitors that closely fit within the substrate binding region is proposed to be a strategy to avoid drug resistance.Recent findings-Co-crystal structures of HIV-1 protease with its substrates define an overlapping substrate binding region, or substrate envelope. Novel HIV-1 protease inhibitors that were designed to fit within this substrate envelope, were found to retain high binding affinity and have a flat binding profile against a panel of drug resistant HIV-1 proteases.Summary-Avoiding drug resistance needs to be considered in the initial design of inhibitors to quickly evolving targets such as HIV-1 protease. Using a detailed knowledge of substrate binding appears to be a promising strategy for achieving this goal to obtain robust HIV-1 protease inhibitors.

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“…The design approach is based in part upon the hypothesis that inhibitors that bind within a consensus envelope of bound substrate peptides are more likely to retain affinity for clinically relevant mutants 9,10,11,12,13. Many of the HIV protease inhibitors synthesized and tested in the course of this effort possess a common chemical scaffold with three variable substituent positions (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Additivity in the Analysis and Design of HIV Protease Inhibitors

et al. 2009

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We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors, whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridgeregression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.

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Substrate Envelope and Drug Resistance: Crystal Structure of RO1 in Complex with Wild-Type Human Immunodeficiency Virus Type 1 Protease

Cited by 34 publications

References 18 publications

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors

Additivity in the Analysis and Design of HIV Protease Inhibitors

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