Darunavir (Prezista, TMC114): From Bench to Clinic, Improving Treatment Options for HIV‐Infected Patients

Béthune, Marie‐Pierre de; Sekar, Vanitha; Spinosa‐Guzman, Sabrina; Vanstockem, Marc; Meyer, Sandra De; Wigerinck, Piet; Lefebvre, E.

doi:10.1002/9780470929353.ch3

Cited by 12 publications

(25 citation statements)

References 47 publications

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“…cious in suppressing HIV-1 replicationa nd showing significant clinicalb enefits to HIV/AIDS patients. [9,10] Darunavir has emergeda saw idely used first-line therapy for rescue treatment. [11,12] Its exceptional resistance profile is due to ad ual mechanism of action as it inhibits HIV-1 protease and inhibits dimerization of HIV-1 protease monomers.…”

Section: Introductionmentioning

confidence: 99%

“…HIV‐1 protease inhibitor (PI) drugs block HIV‐1 protease and generate morphologically immature and noninfectious virions . Darunavir ( 1 , Figure ), the latest FDA‐approved PI, has been highly efficacious in suppressing HIV‐1 replication and showing significant clinical benefits to HIV/AIDS patients . Darunavir has emerged as a widely used first‐line therapy for rescue treatment .…”

Section: Introductionmentioning

confidence: 99%

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Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies

et al. 2019

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We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV‐1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT‐2 cell lines. Inhibitors bearing bis‐THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2′ ligands, showed very potent HIV‐1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide‐derived inhibitors which showed good antiviral IC50 value. Boronic acid derived inhibitor with bis‐THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2‐Crn‐THF ligand also showed potent enzyme Ki but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug‐resistant HIV‐1 variants. One of the inhibitors maintained good antiviral activity against HIVDRVRP20 and HIVDRVRP30 viruses. We have determined high resolution X‐ray structures of two synthetic inhibitors bound to HIV‐1 protease and obtained molecular insight into the ligand‐binding site interactions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies

et al. 2019

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“…18,20 We incorporated a stereochemically defined bis -tetrahydrofuran ( bis -THF) ligand in Darunavir (DRV 1 , Figure 1) to promote hydrogen bonding interactions with Asp29 and Asp30 backbone NHs in the S2-subsite. 16,21–24 Our structure-based design strategies also created other intriguing PIs with ligands such as cyclopentyl-tetrahydrofuran ( Cp -THF), tetrahydropyrano-tetrahydrofuran ( Tp -THF), tris -tetrahydrofuran ( Tris -THF), and crown -tetrahydrofuran ( Crn -THF). 18,25,26 These inhibitors have been shown to bind extensively with the backbone atoms of active site of HIV-1 protease and maintain robust antiviral activity against a wide range of multidrug-resistant HIV-1 variants.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X-ray Structural Analysis

et al. 2018

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The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands, are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

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“…7,8 The last FDA approved protease inhibitor, darunavir ( 1 , Figure 1), has significantly improved properties. 9,10 Darunavir has been shown to maintain excellent potency against a broad-spectrum of highly multidrug-resistant HIV-1 variants. 11,12 Darunavir and related derivative TMC126 ( 2 ) were specifically designed to promote extensive hydrogen-bonding interactions with HIV-1 protease backbone atoms.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

Ghosh

Jadhav

Simpson

et al. 2018

European Journal of Medicinal Chemistry

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We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.

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Darunavir (Prezista, TMC114): From Bench to Clinic, Improving Treatment Options for HIV‐Infected Patients

Cited by 12 publications

References 47 publications

Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies

Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies

Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X-ray Structural Analysis

Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

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