HIV Protease Inhibitors Possessing a Novel, High-Affinity, and Achiral P1'/P2' Ligand with a Unique Pattern of in Vitro Resistance. Importance of a Conformationally-Restricted Template in the Design of Enzyme Inhibitors

Prasad, J. V. N. Vara; Lunney, Elizabeth A.; Ferguson, Donna; Tummino, Peter J.; Rubin, John R.; Reyner, Eric L.; Stewart, Barbra H.; Guttendorf, Robert; Domagala, John M.

doi:10.1021/ja00150a005

Cited by 34 publications

(25 citation statements)

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“…Iterative cycles of structure-based design led to Tipranavir 20 (PNU-140690, clinical trials), a potent and orally bioavailable nonpeptidic protease inhibitor [82][83][84][85][86][87][88]. (further reading: Parke-Davis [89][90][91][92][93][94][95][96][97]).…”

Section: Screening Approachmentioning

confidence: 99%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as potential targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

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Section: Screening Approachmentioning

confidence: 99%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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“…The BPS mutant, which was termed phenylpyrone synthase (PPS), has so far not been found as a naturally occurring type III PKS variation. Interestingly, derivatives of the PPS product are highly potent anti-human immunodeficiency virus agents (14).…”

mentioning

confidence: 99%

A Single Amino Acid Substitution Converts Benzophenone Synthase into Phenylpyrone Synthase

Klundt

Bocola

Lütge

et al. 2009

Journal of Biological Chemistry

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“…The condensed 5‐alkyl‐6‐hydoxy‐4‐pyrimidone and 5‐arylthio‐6‐hydoxy‐4‐pyrimidone show some anti‐inflammatory activity . Some of the 3‐alkylthio‐4‐hydroxy‐2‐pyrones are effective HIV‐protease inhibitors . This and the known fungicidal and antiseptic activity of thiuram (tetramethylthiuram disulfide) and disulfiram (antabuse, tetraethylthiuram disulfide) prompted us to synthesize sulfenyl derivatives of 4‐hydroxy‐2,5‐pyranopyridones, 4‐hydroxy‐2‐pyridones, and 4‐hydroxy‐coumarins.…”

Section: Introductionmentioning

confidence: 99%

A Simple, Convenient One‐Pot Synthesis of Dithio‐Carbamide Derivatives of Heterocyclic 1,3‐Dicarbonyl Systems

Nikam¹,

Kappe

2016

Journal of Heterocyclic Chem

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A various new dithi‐ocarbamides were synthesized from heterocyclic six‐membered 1,3‐dicarbonyl systems, such as 4‐hydroxy‐2,5‐pyranopyridines, 4‐hydroxy‐2‐pyridones, 4‐Hydroxy‐2‐quinolones, 4‐hydroxy‐coumarins, and 4‐hydroxy‐1‐methyl‐2‐quinolones. The dicarbonyl compounds in the presence of anhydrous potassium carbonate in dimethyformamide react with tetraalkylthiuram disulfides to yield 3‐dialkylaminothiocarbonylthio derivatives through a simple, convenient one‐pot reaction. The structures were confirmed by using IR, NMR, and elemental analysis.

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HIV Protease Inhibitors Possessing a Novel, High-Affinity, and Achiral P1'/P2' Ligand with a Unique Pattern of in Vitro Resistance. Importance of a Conformationally-Restricted Template in the Design of Enzyme Inhibitors

Cited by 34 publications

References 1 publication

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Approaches to the Design of Effective HIV-1 Protease Inhibitors

A Single Amino Acid Substitution Converts Benzophenone Synthase into Phenylpyrone Synthase

A Simple, Convenient One‐Pot Synthesis of Dithio‐Carbamide Derivatives of Heterocyclic 1,3‐Dicarbonyl Systems

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