Lysine sulfonamides as novel HIV-Protease inhibitors: optimization of the Nε -acyl-phenyl spacer

Stranix, Brent R.; Sauvé, Gilles; Bouzide, Abderrahim; Côté, Alexandre; Sévigny, Guy; Yelle, Jocelyn

doi:10.1016/j.bmcl.2003.09.058

Cited by 18 publications

(7 citation statements)

References 10 publications

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“…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]. PIs with improved resistance profiles were also developed using a solvent anchoring approach [27], and utilizing a new lysine sulfonamide-based molecular core [28]. Another design strategy incorporates substrate envelope constraints into structure-based design and led to the discovery of novel highly potent PIs that are less susceptible to drug-resistance [29].…”

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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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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“…Thus, a priority in antiretroviral-drug research is now the development of new HIV inhibitors that exhibit distinct resistance profiles to provide patients with alternatives in combi-nation therapy. To tackle this challenge, a drug discovery program was established that integrated viral resistance directly into the screening process (26,(28)(29)(30). We present the biochemical and virological characterization of a new PI, termed PL-100, that emerged from this program.…”

mentioning

confidence: 99%

In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

Dandache

Sévigny

Yelle

et al. 2007

Antimicrob Agents Chemother

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Despite the success of highly active antiretroviral therapy, the current emergence and spread of drugresistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original L-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K i , ϳ36 pM, and 50% effective concentration [EC 50 ], ϳ16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC 50 for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.

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“…Subsequent rounds of chemical modifications led to the discovery of a series of potent lysine sulfonamide protease inhibitors [47][48][49][50]. One of the most promising inhibitors of these series, PPL-100, has been licensed to Merck and was in phase 1 clinical trial as MK-8122.…”

Section: Lysine Sulfonamides As An Example Of a Screening Approachmentioning

confidence: 99%

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

Gulnik

Eissenstat

2008

Current Opinion in HIV and AIDS

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Several theories on how to design HIV protease inhibitors with improved resistance profiles have been proposed during the review period. The general concepts that are incorporated into most design strategies include maximizing the interactions with the backbone and conserved side chains of the enzyme while minimizing inhibitor size and maintaining conformational flexibility to allow for modified binding modes.

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Lysine sulfonamides as novel HIV-Protease inhibitors: optimization of the Nε -acyl-phenyl spacer

Cited by 18 publications

References 10 publications

Molecular Basis for Drug Resistance in HIV-1 Protease

Molecular Basis for Drug Resistance in HIV-1 Protease

In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

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

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