Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease

Nalam, M.N.L.; Peeters, Anik; Jonckers, Tim H. M.; Dierynck, Inge; Schiffer, Celia A.

doi:10.1128/jvi.00799-07

Cited by 33 publications

(30 citation statements)

References 30 publications

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“…Other strategies[53–57] of restricting inhibitors to predominantly interact only with backbone or conserved side chains to avoid resistance are not necessarily mutually exclusive with this theory, in fact both cases may be true. Ideally the strategy of using such theories as the substrate envelope to avoid drug resistance coupled with the use of new scaffolds like the lysine sulfonomides [58,59] will result in novel inhibitors that avoid the need for boosting and reduce other long-term side effects.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The protease was over-expressed and purified mainly using the previous protocol (Nalam et al 2007). Data was recorded using a conventional CPMG phase scheme ( XX – XX ) with delays of 0, 8, 16, 24, 32, 48, and 64 ms. Data were recorded by employing the same r.f.…”

Section: Methodsmentioning

confidence: 99%

Quantitative comparison of errors in 15N transverse relaxation rates measured using various CPMG phasing schemes

et al. 2012

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Nitrogen-15 Carr-Purcell-Meiboom-Gill (CPMG) transverse relaxation experiment are widely used to characterize protein backbone dynamics and chemical exchange parameters. Although an accurate value of the transverse relaxation rate, R2, is needed for accurate characterization of dynamics, the uncertainty in the R2 value depends on the experimental settings and the details of the data analysis itself. Here, we present an analysis of the impact of CPMG pulse phase alternation on the accuracy of the 15N CPMG R2. Our simulations show that R2 can be obtained accurately for a relatively wide spectral width, either using the conventional phase cycle or using phase alternation when the r.f. pulse power is accurately calibrated. However, when the r.f. pulse is miscalibrated, the conventional CPMG experiment exhibits more significant uncertainties in R2 caused by the off-resonance effect than does the phase alternation experiment. Our experiments show that this effect becomes manifest under the circumstance that the systematic error exceeds that arising from experimental noise. Furthermore, our results provide the means to estimate practical parameter settings that yield accurate values of 15N transverse relaxation rates in the both CPMG experiments.

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“…It is rapidly metabolized to its active compound PL‐100 in vivo by hydrolysis. PL‐100 contains a lysine‐based scaffold and forms hydrogen bonds with the flap of the HIV protease via the sulfonamide oxygens, displacing the connecting water molecule . This novel interaction gives the drug a high barrier to resistance and good activity against multidrug‐resistant HIV strains .…”

Section: Inhibitors Of Proteases From Microbial Pathogensmentioning

confidence: 99%

Proteases and protease inhibitors in infectious diseases

Agbowuro

Huston

Gamble

et al. 2017

Medicinal Research Reviews

165

103

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There are numerous proteases of pathogenic organisms that are currently targeted for therapeutic intervention along with many that are seen as potential drug targets. This review discusses the chemical and biological makeup of some key druggable proteases expressed by the five major classes of disease causing agents, namely bacteria, viruses, fungi, eukaryotes, and prions. While a few of these enzymes including HIV protease and HCV NS3-4A protease have been targeted to a clinically useful level, a number are yet to yield any clinical outcomes in terms of antimicrobial therapy. A significant aspect of this review discusses the chemical and pharmacological characteristics of inhibitors of the various proteases discussed. A total of 25 inhibitors have been considered potent and safe enough to be trialed in humans and are at different levels of clinical application. We assess the mechanism of action and clinical performance of the protease inhibitors against infectious agents with their developmental strategies and look to the next frontiers in the use of protease inhibitors as anti-infective agents.

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Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease

Cited by 33 publications

References 30 publications

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

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

Quantitative comparison of errors in 15N transverse relaxation rates measured using various CPMG phasing schemes

Proteases and protease inhibitors in infectious diseases

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