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A target within the target: probing cruzain's P1' site to define structural determinants for the Chagas' disease protease.

Brinen LS, Hansell E, Cheng J, Roush WR, McKerrow JH, Fletterick RJ
Structure 8 831-40 (2000)
Related entries: 1f29, 1f2a, 1f2c

Cited: 54 times
EuropePMC logo PMID: 10997902

Abstract

Background

Cysteine proteases of the papain superfamily are present in nearly all groups of eukaryotes and play vital roles in a wide range of biological processes and diseases, including antigen and hormone processing, bacterial infection, arthritis, osteoporosis, Alzheimer's disease and cancer-cell invasion. Because they are critical to the life-cycle progression of many pathogenic protozoa, they represent potential targets for selective inhibitors. Chagas' disease, the leading cause of death due to heart disease in Latin American countries, is transmitted by Trypanosoma cruzi. Cruzain is the major cysteine protease of T cruzi and has been the target of extensive structure-based drug design.

Results

High-resolution crystal structures of cruzain bound to a series of potent phenyl-containing vinyl-sulfone, sulfonate and sulfonamide inhibitors have been determined. The structures show a consistent mode of interaction for this family of inhibitors based on a covalent Michael addition formed at the enzyme's active-site cysteine, hydrophobic interactions in the S2 substrate-binding pocket and a strong constellation of hydrogen bonding in the S1' region.

Conclusion

The series of vinyl-sulfone-based inhibitors examined in complex with cruzain was designed to probe recognition and binding potential of an aromatic-rich region of the enzyme. Analysis of the interactions formed shows that aromatic interactions play a less significant role, whereas the strength and importance of hydrogen bonding in the conformation adopted by the inhibitor upon binding to the enzyme was highlighted. A derivative of one inhibitor examined is currently under development as a therapeutic agent against Chagas' disease.

Reviews - 1f2b mentioned but not cited (1)

  1. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 (2016)

Articles - 1f2b mentioned but not cited (4)

  1. In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi. Chen YT, Brinen LS, Kerr ID, Hansell E, Doyle PS, McKerrow JH, Roush WR. PLoS Negl Trop Dis 4 (2010)
  2. The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites. Santos VC, Oliveira AER, Campos ACB, Reis-Cunha JL, Bartholomeu DC, Teixeira SMR, Lima APCA, Ferreira RS. Sci Rep 11 18231 (2021)
  3. Cruzain structures: apocruzain and cruzain bound to S-methyl thiomethanesulfonate and implications for drug design. Barbosa da Silva E, Dall E, Briza P, Brandstetter H, Ferreira RS. Acta Crystallogr F Struct Biol Commun 75 419-427 (2019)
  4. Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents. Cianni L, Lemke C, Gilberg E, Feldmann C, Rosini F, Rocho FDR, Ribeiro JFR, Tezuka DY, Lopes CD, de Albuquerque S, Bajorath J, Laufer S, Leitão A, Gütschow M, Montanari CA. PLoS Negl Trop Dis 14 e0007755 (2020)


Reviews citing this publication (6)

  1. Biological roles of proteases in parasitic protozoa. Klemba M, Goldberg DE. Annu. Rev. Biochem. 71 275-305 (2002)
  2. Congopain from Trypanosoma congolense: drug target and vaccine candidate. Lalmanach G, Boulangé A, Serveau C, Lecaille F, Scharfstein J, Gauthier F, Authié E. Biol. Chem. 383 739-749 (2002)
  3. Looking at the proteases from a simple perspective. Castro HC, Abreu PA, Abreu PA, Geraldo RB, Martins RC, dos Santos R, Loureiro NI, Cabral LM, Rodrigues CR. J. Mol. Recognit. 24 165-181 (2011)
  4. Cruzain inhibitors: efforts made, current leads and a structural outlook of new hits. Martinez-Mayorga K, Byler KG, Ramirez-Hernandez AI, Terrazas-Alvares DE. Drug Discov. Today 20 890-898 (2015)
  5. Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host. Sueth-Santiago V, Decote-Ricardo D, Morrot A, Freire-de-Lima CG, Lima ME. World J Biol Chem 8 57-80 (2017)
  6. Three-dimensional structures in the design of therapeutics targeting parasitic protozoa: reflections on the past, present and future. Hol WG. Acta Crystallogr F Struct Biol Commun 71 485-499 (2015)

Articles citing this publication (43)

  1. Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design. Greenbaum DC, Arnold WD, Lu F, Hayrapetian L, Baruch A, Krumrine J, Toba S, Chehade K, Brömme D, Kuntz ID, Bogyo M. Chem. Biol. 9 1085-1094 (2002)
  2. Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Caffrey CR, Hansell E, Lucas KD, Brinen LS, Alvarez Hernandez A, Cheng J, Gwaltney SL, Roush WR, Stierhof YD, Bogyo M, Steverding D, McKerrow JH. Mol. Biochem. Parasitol. 118 61-73 (2001)
  3. Vinyl sulfones as antiparasitic agents and a structural basis for drug design. Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, Pandey KC, Caffrey CR, Legac J, Hansell E, McKerrow JH, Craik CS, Rosenthal PJ, Brinen LS. J. Biol. Chem. 284 25697-25703 (2009)
  4. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL. J Biol Chem 281 25425-25437 (2006)
  5. Cysteine proteinases from distinct cellular compartments are recruited to phagocytic vesicles by Entamoeba histolytica. Que X, Brinen LS, Perkins P, Herdman S, Hirata K, Torian BE, Rubin H, McKerrow JH, Reed SL. Mol. Biochem. Parasitol. 119 23-32 (2002)
  6. Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, Holzgrabe U, Caffrey CR, Ponte-Sucre A, Moll H, Stich A, Schirmeister T. Bioorg. Med. Chem. Lett. 16 2753-2757 (2006)
  7. Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease. Choe Y, Brinen LS, Price MS, Engel JC, Lange M, Grisostomi C, Weston SG, Pallai PV, Cheng H, Hardy LW, Hartsough DS, McMakin M, Tilton RF, Baldino CM, Craik CS. Bioorg. Med. Chem. 13 2141-2156 (2005)
  8. Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy. Brak K, Kerr ID, Barrett KT, Fuchi N, Debnath M, Ang K, Engel JC, McKerrow JH, Doyle PS, Brinen LS, Ellman JA. J. Med. Chem. 53 1763-1773 (2010)
  9. Synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazones, designed as cruzain inhibitors candidates. Romeiro NC, Aguirre G, Hernández P, González M, Cerecetto H, Aldana I, Pérez-Silanes S, Monge A, Barreiro EJ, Lima LM. Bioorg. Med. Chem. 17 641-652 (2009)
  10. Crystal structures of reversible ketone-Based inhibitors of the cysteine protease cruzain. Huang L, Brinen LS, Ellman JA. Bioorg. Med. Chem. 11 21-29 (2003)
  11. Potent second generation vinyl sulfonamide inhibitors of the trypanosomal cysteine protease cruzain. Roush WR, Cheng J, Knapp-Reed B, Alvarez-Hernandez A, McKerrow JH, Hansell E, Engel JC. Bioorg. Med. Chem. Lett. 11 2759-2762 (2001)
  12. The cathepsin L of Toxoplasma gondii (TgCPL) and its endogenous macromolecular inhibitor, toxostatin. Huang R, Que X, Hirata K, Brinen LS, Lee JH, Hansell E, Engel J, Sajid M, Reed S. Mol. Biochem. Parasitol. 164 86-94 (2009)
  13. Probing the structure of falcipain-3, a cysteine protease from Plasmodium falciparum: comparative protein modeling and docking studies. Sabnis YA, Desai PV, Rosenthal PJ, Avery MA. Protein Sci. 12 501-509 (2003)
  14. The crystal structure of human cathepsin F and its implications for the development of novel immunomodulators. Somoza JR, Palmer JT, Ho JD. J. Mol. Biol. 322 559-568 (2002)
  15. Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases. Bryant C, Kerr ID, Debnath M, Ang KK, Ratnam J, Ferreira RS, Jaishankar P, Zhao D, Arkin MR, McKerrow JH, Brinen LS, Renslo AR. Bioorg. Med. Chem. Lett. 19 6218-6221 (2009)
  16. Structural basis for inhibition of cathepsin B drug target from the human blood fluke, Schistosoma mansoni. Jílková A, Rezácová P, Lepsík M, Horn M, Váchová J, Fanfrlík J, Brynda J, McKerrow JH, Caffrey CR, Mares M. J. Biol. Chem. 286 35770-35781 (2011)
  17. Homology modeling of falcipain-2: validation, de novo ligand design and synthesis of novel inhibitors. Sabnis Y, Rosenthal PJ, Desai P, Avery MA. J. Biomol. Struct. Dyn. 19 765-774 (2002)
  18. Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes. Jaishankar P, Hansell E, Zhao DM, Doyle PS, McKerrow JH, Renslo AR. Bioorg. Med. Chem. Lett. 18 624-628 (2008)
  19. Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents. Yang PY, Wang M, Li L, Wu H, He CY, Yao SQ. Chemistry 18 6528-6541 (2012)
  20. Comparison of the specificity, stability and individual rate constants with respective activation parameters for the peptidase activity of cruzipain and its recombinant form, cruzain, from Trypanosoma cruzi. Judice WA, Cezari MH, Lima AP, Scharfstein J, Chagas JR, Tersariol IL, Juliano MA, Juliano L. Eur. J. Biochem. 268 6578-6586 (2001)
  21. Computational identification of uncharacterized cruzain binding sites. Durrant JD, Keränen H, Wilson BA, McCammon JA. PLoS Negl Trop Dis 4 e676 (2010)
  22. Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations. Sulpizi M, Laio A, VandeVondele J, Cattaneo A, Rothlisberger U, Carloni P. Proteins 52 212-224 (2003)
  23. Synthesis of macrocyclic trypanosomal cysteine protease inhibitors. Chen YT, Lira R, Hansell E, McKerrow JH, Roush WR. Bioorg. Med. Chem. Lett. 18 5860-5863 (2008)
  24. Comparative molecular docking of antitrypanosomal natural products into multiple Trypanosoma brucei drug targets. Ogungbe IV, Setzer WN. Molecules 14 1513-1536 (2009)
  25. Novel cruzain inhibitors for the treatment of Chagas' disease. Rogers KE, Keränen H, Durrant JD, Ratnam J, Doak A, Arkin MR, McCammon JA. Chem Biol Drug Des 80 398-405 (2012)
  26. Optimization of anti-Trypanosoma cruzi oxadiazoles leads to identification of compounds with efficacy in infected mice. dos Santos Filho JM, Moreira DR, de Simone CA, Ferreira RS, McKerrow JH, Meira CS, Guimarães ET, Soares MB. Bioorg. Med. Chem. 20 6423-6433 (2012)
  27. Synthesis of Unprecedented Sulfonylated Phosphono-exo-Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes. Frédéric CJ, Tikad A, Fu J, Pan W, Zheng RB, Koizumi A, Xue X, Lowary TL, Vincent SP. Chemistry 22 15913-15920 (2016)
  28. Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors. Wiggers HJ, Rocha JR, Cheleski J, Montanari CA. Mol Inform 30 565-578 (2011)
  29. Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain. Jones BD, Tochowicz A, Tang Y, Cameron MD, McCall LI, Hirata K, Siqueira-Neto JL, Reed SL, McKerrow JH, Roush WR. ACS Med Chem Lett 7 77-82 (2016)
  30. Reversible inhibition of cathepsin L-like proteases by 4-mer pseudopeptides. Lecaille F, Cotton J, McKerrow JH, Ferrer-Di Martino M, Boll-Bataillé E, Gauthier F, Lalmanach G. FEBS Lett. 507 362-366 (2001)
  31. Structural characterization of vivapain-2 and vivapain-3, cysteine proteases from Plasmodium vivax: comparative protein modeling and docking studies. Desai PV, Avery MA. J. Biomol. Struct. Dyn. 21 781-790 (2004)
  32. Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors. Jílková A, Rubešová P, Fanfrlík J, Fajtová P, Řezáčová P, Brynda J, Lepšík M, Mertlíková-Kaiserová H, Emal CD, Renslo AR, Roush WR, Horn M, Caffrey CR, Mareš M. ACS Infect Dis 7 1077-1088 (2021)
  33. Inhibition of cysteine proteases by a natural biflavone: behavioral evaluation of fukugetin as papain and cruzain inhibitor. Assis DM, Gontijo VS, de Oliveira Pereira I, Santos JA, Camps I, Nagem TJ, Ellena J, Izidoro MA, dos Santos Tersariol IL, de Barros NM, Doriguetto AC, dos Santos MH, Juliano MA. J Enzyme Inhib Med Chem 28 661-670 (2013)
  34. Turnover-dependent covalent inactivation of Staphylococcus aureus coenzyme A-disulfide reductase by coenzyme A-mimetics: mechanistic and structural insights. Wallace BD, Edwards JS, Wallen JR, Moolman WJ, van der Westhuyzen R, Strauss E, Redinbo MR, Claiborne A. Biochemistry 51 7699-7711 (2012)
  35. Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations. Martins LC, Torres PHM, de Oliveira RB, Pascutti PG, Cino EA, Ferreira RS. J. Comput. Aided Mol. Des. 32 591-605 (2018)
  36. Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery. Zafar A, Ahmad S, Rizvi A, Ahmad M. PLoS ONE 10 e0123996 (2015)
  37. Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies. Pérez B, Antunes S, Gonçalves LM, Domingos A, Gomes JR, Gomes P, Teixeira C. J. Comput. Aided Mol. Des. 27 823-835 (2013)
  38. Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism. Luchi AM, Villafañe RN, Gómez Chávez JL, Bogado ML, Angelina EL, Peruchena NM. ACS Omega 4 19582-19594 (2019)
  39. Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches. Rampogu S, Lee G, Baek A, Son M, Park C, Zeb A, Yoon SH, Park S, Lee KW. Molecules 23 (2018)
  40. Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis. Lourenço EMG, Di Iório JF, da Silva F, Fialho FLB, Monteiro MM, Beatriz A, Perdomo RT, Barbosa EG, Oses JP, de Arruda CCP, de Souza Júdice WA, Rafique J, de Lima DP. Microorganisms 11 225 (2023)
  41. Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies. Palos I, Lara-Ramirez EE, Lopez-Cedillo JC, Garcia-Perez C, Kashif M, Bocanegra-Garcia V, Nogueda-Torres B, Rivera G. Molecules 22 (2017)
  42. Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival. Rivero CV, Martínez SJ, Novick P, Cueto JA, Salassa BN, Vanrell MC, Li X, Labriola CA, Polo LM, Engman DM, Clos J, Romano PS. Front Cell Infect Microbiol 11 657257 (2021)
  43. Sulfonamide derived from anacardic acid as potential antichagasic: a theoretical approach based on molecular docking, molecular dynamics, and density functional theory calculations. da Silva LP, Almeida-Neto FWQ, Bezerra LL, Silva J, Monteiro NKV, Marinho MM, Dos Santos HS, Teixeira AMR, Marinho ES, de Lima-Neto P. J Mol Model 29 165 (2023)


Related citations provided by authors (1)

  1. The crystal structure of cruzain: a therapeutic target for Chagas' disease.. McGrath ME, Eakin AE, Engel JC, McKerrow JH, Craik CS, Fletterick RJ J Mol Biol 247 251-9 (1995)

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