Development of cell-active non-peptidyl inhibitors of cysteine cathepsins

Dana, Dibyendu; De, Shatarupa; Rathod, Pratikkumar; Gamage, Ranjith K.; Huestis, Juliana; Afzal, Nisar; Zavlanov, Yuriy; Paroly, Suneeta S.; Rotenberg, Susan A.; Subramaniam, G.; Mark, Kevin J.; Chang, Emmanuel J.; Kumar, Shiv Datt

doi:10.1016/j.bmc.2013.03.062

Cited by 17 publications

(6 citation statements)

References 70 publications

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“…An arylsulfonyloxirane warhead was developed in 2013 as a cathepsin B, but the lack of a recognition group led to modest inhibition 80 . Cyclic sulfates have been developed that show selectivity for cathepsin B over calpain, presumably due to the steric hindrance in the calpain active site 81 , 82 .…”

Section: Electrophilic Warheads For Cys Protease Inhibitorsmentioning

confidence: 99%

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Siklos

BenAissa

Thatcher

2015

Acta Pharmaceutica Sinica B

212

169

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Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.

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Section: Electrophilic Warheads For Cys Protease Inhibitorsmentioning

confidence: 99%

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Siklos

BenAissa

Thatcher

2015

Acta Pharmaceutica Sinica B

212

169

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“…SPPS/solution phase synthesis of the NBD-based substrates suited for cysteine-, serine-, and metalloproteases. ZÀ PheÀ ArgÀ AMC [44] Cathepsin S (human) Cysteine ZÀ ValÀ ValÀ ArgÀ NBD (7 b) ZÀ ValÀ ValÀ ArgÀ AMC [45] SARS-CoV 2 M pro Cysteine BocÀ AbuÀ TleÀ LeuÀ GlnÀ NBD (7 c) BocÀ AbuÀ TleÀ LeuÀ GlnÀ AMC [46] S. aureus SrtA Cysteine BzÀ LeuÀ ProÀ AlaÀ ThrÀ GlyÀ NBD (7 d) AbzÀ LeuÀ ProÀ GluÀ ThrÀ GlyÀ Dap(Dnp)À OH [47] SARS-CoV 2 PL pro Cysteine ZÀ ArgÀ LeuÀ ArgÀ GlyÀ GlyÀ NBD (7 e) ZÀ ArgÀ LeuÀ ArgÀ GlyÀ GlyÀ AMC [48] uPA (human) Serine ZÀ GlyÀ GlyÀ ArgÀ NBD (7 f) ZÀ GlyÀ GlyÀ ArgÀ AMC [49] DENV NS2B/NS3 Serine BzÀ NleÀ LysÀ LysÀ ArgÀ NBD (7 g) AcÀ GlyÀ ArgÀ ArgÀ NBD (7 h)…”

Section: Kinetic Characterization Of Ndb-based Substratesmentioning

confidence: 99%

Next Generation of Fluorometric Protease Assays: 7‐Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl‐amides (NBD‐Amides) as Class‐Spanning Protease Substrates

Maus

Müller

Meta

et al. 2023

Chemistry A European J

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Fluorometric assays are one of the most frequently used methods in medicinal chemistry. Over the last 50 years, the reporter molecules for the detection of protease activity have evolved from first-generation colorimetric p-nitroanilides, through FRET substrates, and 7-amino-4-methyl coumarin (AMC)-based substrates. The aim of further substrate development is to increase sensitivity and reduce vulnerability to assay interferences. Herein, we describe a new generation of substrates for protease assays based on 7-nitrobenz-2-oxa-1,3diazol-4-yl-amides (NBD-amides). In this study, we synthesized and tested substrates for 10 different proteases from the serine-, cysteine-, and metalloprotease classes. Enzyme-and substratespecific parameters as well as the inhibitory activity of literature-known inhibitors confirmed their suitability for application in fluorometric assays. Hence, we were able to present NBD-based alternatives for common protease substrates. In conclusion, these NBD substrates are not only less susceptible to common assay interference, but they are also able to replace FRET-based substrates with the requirement of a prime site amino acid residue.

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“…Therefore, research on non-peptidyl drugs has become an important aspect in drug research and development. 12,13 Chalcone derivatives (I and II) 14,15 have been reported as inhibitors to cysteine proteases.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory potential of some chalcones on cathepsins B, H and L

Garg

Raghav

2015

RSC Adv.

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Cathepsins, intracellular proteases, are known to be involved in a number of physiological processes ranging from degradation of extracellular proteins, prohormone processing, progressions of atherosclerosis etc. High levels of cathepsins have also been indicated in various pathological conditions like arthritis, cancer etc. One of the reasons for these elevated levels is attributed to decrease in inhibitor concentration. Therefore, the work on the identification of small molecular weight compounds as inhibitors of cysteine proteases is of great therapeutic significance. In the present work, we report synthesis of a small library of chalcones and their study as inhibitors to cysteine proteases. After a preliminary screening of the compounds as inhibitors to cysteine proteases in general, studies were carried out to evaluate their inhibitory effects on cathepsin B, H and L. The most potent inhibitors among all the compounds were nitro substituted compounds for cathepsin B and cathepsin L and chloro substituted compounds for cathepsin H, respectively.

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Development of cell-active non-peptidyl inhibitors of cysteine cathepsins

Cited by 17 publications

References 70 publications

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Next Generation of Fluorometric Protease Assays: 7‐Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl‐amides (NBD‐Amides) as Class‐Spanning Protease Substrates

Inhibitory potential of some chalcones on cathepsins B, H and L

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