Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors:  Synthesis, Structure−Activity Relationships, and X-ray Crystal Structure Studies

1998 ◽  
Vol 41 (9) ◽  
pp. 1446-1455 ◽  
Author(s):  
Prabhakar K. Jadhav ◽  
Francis J. Woerner ◽  
Patrick Y. S. Lam ◽  
C. Nicholas Hodge ◽  
Charles J. Eyermann ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protease Inhibitors ◽  
X Ray ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Hiv 1

scholarly journals Synergistic Lethality of a Binary Inhibitor ofMycobacterium tuberculosisKasA

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Pradeep Kumar ◽  
Glenn C. Capodagli ◽  
Divya Awasthi ◽  
Riju Shrestha ◽  
Karishma Maharaja ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Substrate Binding ◽  
Content Type ◽  
X Ray ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Transcriptional Pattern

ABSTRACTWe report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) inMycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented thein vitroactivity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model ofM. tuberculosisinfection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCECell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors ofMycobacterium tuberculosisKasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

scholarly journals Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure

2011 ◽  
Vol 54 (16) ◽  
pp. 5890-5901 ◽  
Author(s):  
Arun K. Ghosh ◽  
Bruno D. Chapsal ◽  
Garth L. Parham ◽  
Melinda Steffey ◽  
Johnson Agniswamy ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protease Inhibitors ◽  
Biological Evaluation ◽  
X Ray ◽  
Hiv 1
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