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A class of allosteric caspase inhibitors identified by high-throughput screening.

Feldman T, Kabaleeswaran V, Jang SB, Antczak C, Djaballah H, Wu H, Jiang X
Mol Cell 47 585-95 (2012)
Cited: 24 times
EuropePMC logo PMID: 22795132

Abstract

Caspase inhibition is a promising approach for treating multiple diseases. Using a reconstituted assay and high-throughput screening, we identified a group of nonpeptide caspase inhibitors. These inhibitors share common chemical scaffolds, suggesting the same mechanism of action. They can inhibit apoptosis in various cell types induced by multiple stimuli; they can also inhibit caspase-1-mediated interleukin generation in macrophages, indicating potential anti-inflammatory application. While these compounds inhibit all the tested caspases, kinetic analysis indicates they do not compete for the catalytic sites of the enzymes. The cocrystal structure of one of these compounds with caspase-7 reveals that it binds to the dimerization interface of the caspase, another common structural element shared by all active caspases. Consistently, biochemical analysis demonstrates that the compound abates caspase-8 dimerization. Based on these kinetic, biochemical, and structural analyses, we suggest that these compounds are allosteric caspase inhibitors that function through binding to the dimerization interface of caspases.

Reviews - 4fea mentioned but not cited (1)

  1. Small Molecule Active Site Directed Tools for Studying Human Caspases. Poreba M, Szalek A, Kasperkiewicz P, Rut W, Salvesen GS, Drag M. Chem Rev 115 12546-12629 (2015)

Articles - 4fea mentioned but not cited (2)

  1. A class of allosteric caspase inhibitors identified by high-throughput screening. Feldman T, Kabaleeswaran V, Jang SB, Antczak C, Djaballah H, Wu H, Jiang X. Mol Cell 47 585-595 (2012)
  2. Kaempferol mitigates Endoplasmic Reticulum Stress Induced Cell Death by targeting caspase 3/7. Abdullah A, Ravanan P. Sci Rep 8 2189 (2018)


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  1. Harnessing allostery: a novel approach to drug discovery. Lu S, Li S, Zhang J. Med Res Rev 34 1242-1285 (2014)
  2. Recent computational advances in the identification of allosteric sites in proteins. Lu S, Huang W, Zhang J. Drug Discov Today 19 1595-1600 (2014)
  3. Mechanism-based management for mucositis: option for treating side effects without compromising the efficacy of cancer therapy. Kwon Y. Onco Targets Ther 9 2007-2016 (2016)
  4. A Perspective - can copper complexes be developed as a novel class of therapeutics? Wehbe M, Leung AWY, Abrams MJ, Orvig C, Bally MB. Dalton Trans 46 10758-10773 (2017)
  5. Structure-based inhibition of protein-protein interactions. Watkins AM, Arora PS. Eur J Med Chem 94 480-488 (2015)
  6. The Role of Caspase-2 in Regulating Cell Fate. Vigneswara V, Ahmed Z. Cells 9 E1259 (2020)
  7. Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part II: Future compounds against influenza virus. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. J Prev Med Hyg 55 109-129 (2014)
  8. Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors. Feng Z, Hu G, Ma S, Xie XQ. AAPS J 17 1080-1095 (2015)
  9. Modulating caspase activity: beyond the active site. Murray J, Renslo AR. Curr Opin Struct Biol 23 812-819 (2013)
  10. Mapping oncogenic protein interactions for precision medicine. Sharifi Tabar M, Francis H, Yeo D, Bailey CG, Rasko JEJ. Int J Cancer 151 7-19 (2022)
  11. Mechanisms of Gasdermin Recognition by Proteases. Liu Z, Busscher BM, Storl-Desmond M, Xiao TS. J Mol Biol 434 167274 (2022)
  12. Essential Oils and Their Compounds as Potential Anti-Influenza Agents. Oriola AO, Oyedeji AO. Molecules 27 7797 (2022)
  13. Regulation of Peptidase Activity beyond the Active Site in Human Health and Disease. Obaha A, Novinec M. Int J Mol Sci 24 17120 (2023)

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  1. ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks. Shen Q, Wang G, Li S, Liu X, Lu S, Chen Z, Song K, Yan J, Geng L, Huang Z, Huang W, Chen G, Zhang J. Nucleic Acids Res 44 D527-35 (2016)
  2. A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases. Dagbay K, Eron SJ, Serrano BP, Velázquez-Delgado EM, Zhao Y, Lin D, Vaidya S, Hardy JA. Methods Enzymol 544 215-249 (2014)
  3. Inhibition of caspases protects mice from radiation-induced oral mucositis and abolishes the cleavage of RNA-binding protein HuR. Talwar S, House R, Sundaramurthy S, Balasubramanian S, Yu H, Palanisamy V. J Biol Chem 289 3487-3500 (2014)
  4. Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis. MacPherson DJ, Mills CL, Ondrechen MJ, Hardy JA. J Biol Chem 294 71-88 (2019)
  5. Allosteric Tuning of Caspase-7: A Fragment-Based Drug Discovery Approach. Vance NR, Gakhar L, Spies MA. Angew Chem Int Ed Engl 56 14443-14447 (2017)
  6. Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases. Krishna Deepak RNV, Abdullah A, Talwar P, Fan H, Ravanan P. Proteins 86 1202-1210 (2018)
  7. Microfluidic deep mutational scanning of the human executioner caspases reveals differences in structure and regulation. Roychowdhury H, Romero PA. Cell Death Discov 8 7 (2022)
  8. The impact of cycleanine in cancer research: a computational study. Nwaefulu ON, Al-Shar'i NA, Owolabi JO, Sagineedu SR, Woei LC, Wai LK, Islam MK, Jayanthi S, Stanslas J. J Mol Model 28 340 (2022)


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