Approaches to the design of HIV protease inhibitors with improved resistance profiles

Gulnik, Sergei V.; Eissenstat, Michael A.

doi:10.1097/coh.0b013e328313911d

Cited by 17 publications

(10 citation statements)

References 70 publications

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“…Seven of the nine FDA approved drugs are 2-3 orders of magnitude weaker inhibitors of WT protease ( K i = 46–284 pM), while two are low picomolar binders (LPV and DRV, K i = 5 pM). The precise measurements of K i values in the low pM range using standard biochemical assays are limited (Gulnik and Eissenstat, 2008; Kuzmi&Ccaron, 1996; Miller, et al, 2006). This makes direct comparison of new PIs with DRV, and each other, challenging, as all have K i values in the low pM range.…”

Section: Resultsmentioning

confidence: 99%

“…Various strategies have been used to develop new antiviral PI therapies against drug resistant HIV, including increasing the plasma levels of existing PIs by using a boosting agent (Kempf, et al, 1997; Youle, 2007; Zeldin and Petruschke, 2004) and developing new PIs using structure-based drug design (Ghosh, et al, 2008; Gulnik and Eissenstat, 2008; Nalam and Schiffer, 2008; Wensing, et al, 2010). The design strategy to maximize the number of hydrogen bonds with the protease backbone led to the development of highly potent PIs active against drug-resistant HIV (Ghosh, et al, 2011; Ghosh, et al, 2008; Ghosh, et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

Nalam

Ali

Reddy

et al. 2013

Chemistry & Biology

105

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Summary The rapid evolution of HIV under selective drug pressure has led to multi-drug 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 as a mutation impacting 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 different clades of HIV as well as a panel of 12 drug resistant viral strains. The substrate envelope model proves to be a powerful strategy to develop potent and robust inhibitors that avoid drug resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

Nalam

Ali

Reddy

et al. 2013

Chemistry & Biology

105

View full text Add to dashboard Cite

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“…Generally, the design of novel HIV PIs includes efforts to minimize the inhibitor molecular weight, maximize its interactions with the backbone of the PR binding cleft while maintaining flexibility for better fit to the variable binding clefts of PR resistant species [89]. These general principles are being used by scientists from industry and academia in their efforts to design the next generation of HIV PIs.…”

Section: Other Non-peptidic Hiv Protease Active Site Inhibitorsmentioning

confidence: 99%

Current and Novel Inhibitors of HIV Protease

Pokorná

Machala

Řezáčová

et al. 2009

Viruses

100

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The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR. The potential of these novel compounds to open new way to the rational drug design of human viruses is critically assessed.

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“…Moreover, newly infected patients are infected with resistant viruses which are an added challenge in the treatment of HIV infections. Various strategies have been used to develop new antiviral therapies against drug-resistant HIV, including increasing the plasma levels of existing PIs by using a boosting agent [22] and developing new PIs using structure-based drug design [4,23–25]. Among different approaches, one design strategy maximizes the number of hydrogen bonds with the protease backbone and led to the development of highly potent PIs active against drug-resistant HIV [25,26].…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for Drug Resistance in HIV-1 Protease

Ali

Bandaranayake

Cai

et al. 2010

Viruses

133

118

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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 of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

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Approaches to the design of HIV protease inhibitors with improved resistance profiles

Cited by 17 publications

References 70 publications

Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

Current and Novel Inhibitors of HIV Protease

Molecular Basis for Drug Resistance in HIV-1 Protease

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