From Poor Substrates to Good Inhibitors:  Design of Inhibitors for Serine and Thiol Proteases

Baggio, Rick; Shi, Yugen; Yq, Wu; Abeles,

doi:10.1021/bi952879e

Cited by 34 publications

(38 citation statements)

References 5 publications

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“…However, these compounds do bear structural resemblance to aza-peptides [22][23][24] (e.g., A; Fig. 2), 25 examples, of which have been reported to exhibit cysteine protease inhibitory activity through a 130 mechanism involving attack by the active site cysteine on the carbamate carbonyl.…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

Myers

Shah

Diamond

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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Library samples containing 2,5-disubstituted oxadiazoles were identified as potent hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) directed at discovering inhibitors of cathepsin L. However, when synthesized in pure form, the putative actives were found to be devoid of biological activity. Analyses by LC-MS of original library samples indicated the presence of a number of impurities, in addition to the oxadiazoles. Synthesis and bioassay of the probable impurities led to the identification of a thiocarbazate that likely originated via ring opening of the oxadiazole. Previously unknown, thiocarbazates (-)-11 and (-)-12 were independently synthesized as single enantiomers and found to inhibit cathepsin 20 L in the low nanomolar range. Abstract-Library samples containing 2,5-disubstituted oxadiazoles were identified as potent hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) directed at discovering inhibitors of cathepsin L. However, when synthesized in pure form, the putative actives were found to be devoid of biological activity. Analyses by LC-MS of original library samples indicated the presence of a number of impurities, in addition to the oxadiazoles. Synthesis and bioassay of the probable impurities led to the identification of a thiocarbazate that likely originated via ring opening of the oxadiazole. Previously unknown, thiocarbazates (À)-11 and (À)-12 were independently synthesized as single enantiomers and found to inhibit cathepsin 20

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Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

Myers

Shah

Diamond

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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“…It is unknown whether other amino acid residues enhance Sec reactivity, much like Cys and Ser are activated by His and Asp residues in cysteine and serine proteases (31,32). It is unknown whether other amino acid residues enhance Sec reactivity, much like Cys and Ser are activated by His and Asp residues in cysteine and serine proteases (31,32).…”

Section: Cloning Of a Ptu-insenstive Type I Deiodinase 5157mentioning

confidence: 99%

Characterization of a Propylthiouracil-Insensitive Type I Iodothyronine Deiodinase*

et al. 1997

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Mammalian type I iodothyronine deiodinase (D1) activates and inactivates thyroid hormone by outer ring deiodination (ORD) and inner ring deiodination (IRD), respectively, and is potently inhibited by propylthiouracil (PTU). Here we describe the cloning and characterization of a complementary DNA encoding a PTU-insensitive D1 from teleost fish (Oreochromis niloticus, tilapia). This complementary DNA codes for a protein of 248 amino acids, including a putative selenocysteine (Sec) residue, encoded by a TGA triplet, at position 126. The 3' untranslated region contains two putative Sec insertion sequence (SECIS) elements. Recombinant enzyme expressed in COS-1 cells catalyzes both ORD of T4 and rT3 and IRD of T3 and T3 sulfate with the same substrate specificity as native tilapia D1 (tD1), i.e. rT3 >> T4 > T3 sulfate > T3. Native and recombinant tD1 show equally low sensitivities to inhibition by PTU, iodoacetate, and gold thioglucose compared with the potent inhibitions observed with mammalian D1s. Because the residue 2 positions downstream from Sec is Pro in tD1 and in all (PTU-insensitive) type II and type III iodothyronine deiodinases but Ser in all PTU-sensitive D1s, we prepared the Pro128Ser mutant of tD1. The mutant enzyme showed strongly decreased ORD and somewhat increased IRD activity, but was still insensitive to PTU. These results provide new information about the structure-activity relationship of D1 concerning two characteristic properties, i.e. catalysis of both ORD and IRD, and inhibition by PTU.

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“…SID 26681509 ( Figure 1B), the more stable, Boc-protected S-enantiomer of the ring-opened by-product, proved to be a potent and reversible human cathepsin L inhibitor. Although thiocarbazate inhibitors of cathepsins have not yet been reported, members of the structurally similar class of aza-peptides have been shown to be effective inhibitors of cysteine proteases (Baggio et al, 1996;Magrath and Abeles, 1992;Thompson et al, 1997;Xing and Hanzlik, 1998). Herein, we report the biochemical and biological characterization and molecular docking of SID 26681509, a novel, potent, and selective thiocarbazate inhibitor of human cathepsin L.…”

mentioning

confidence: 99%

Kinetic Characterization and Molecular Docking of a Novel, Potent, and Selective Slow-Binding Inhibitor of Human Cathepsin L

et al. 2008

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A novel small molecule thiocarbazate (PubChem SID 26681509), a potent inhibitor of human cathepsin L (EC 3.4.22.15) with an IC 50 of 56 nM, was developed after a 57,821-compound screen of the National Institutes of Health Molecular Libraries Small Molecule Repository. After a 4-h preincubation with cathepsin L, this compound became even more potent, demonstrating an IC 50 of 1.0 nM. The thiocarbazate was determined to be a slow-binding and slowly reversible competitive inhibitor. Through a transient kinetic analysis for single-step reversibility, inhibition rate constants were k on ϭ 24,000 M Ϫ1 s Ϫ1 and k off ϭ 2.2 ϫ 10 Ϫ5 s Ϫ1 (K i ϭ 0.89 nM). Molecular docking studies were undertaken using the experimentally derived X-ray crystal structure of papain/CLIK-148 (1cvz. pdb). These studies revealed critical hydrogen bonding patterns of the thiocarbazate with key active site residues in papain. The thiocarbazate displayed 7-to 151-fold greater selectivity toward cathepsin L than papain and cathepsins B, K, V, and S with no activity against cathepsin G. The inhibitor demonstrated a lack of toxicity in human aortic endothelial cells and zebrafish. In addition, the thiocarbazate inhibited in vitro propagation of malaria parasite Plasmodium falciparum with an IC 50 of 15.4 M and inhibited Leishmania major with an IC 50 of 12.5 M.

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From Poor Substrates to Good Inhibitors: Design of Inhibitors for Serine and Thiol Proteases

Cited by 34 publications

References 5 publications

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

Characterization of a Propylthiouracil-Insensitive Type I Iodothyronine Deiodinase*

Kinetic Characterization and Molecular Docking of a Novel, Potent, and Selective Slow-Binding Inhibitor of Human Cathepsin L

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