Drug Discovery Efforts to Identify Novel Treatments for Neglected Tropical Diseases - Cysteine Protease Inhibitors


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Abstract

Background:Neglected tropical diseases are a severe burden for mankind, affecting an increasing number of people around the globe. Many of those diseases are caused by protozoan parasites in which cysteine proteases play a key role in the parasite’s pathogenesis.

Objective:In this review article, we summarize the drug discovery efforts of the research community from 2017 - 2022 with a special focus on the optimization of small molecule cysteine protease inhibitors in terms of selectivity profiles or drug-like properties as well as in vivo studies. The cysteine proteases evaluated by this methodology include Cathepsin B1 from Schistosoma mansoni, papain, cruzain, falcipain, and rhodesain.

Methods:Exhaustive literature searches were performed using the keywords "Cysteine Proteases" and "Neglected Tropical Diseases" including the years 2017 - 2022. Overall, approximately 3’000 scientific papers were retrieved, which were filtered using specific keywords enabling the focus on drug discovery efforts.

Results and Conclusion:Potent and selective cysteine protease inhibitors to treat neglected tropical diseases were identified, which progressed to pharmacokinetic and in vivo efficacy studies. As far as the authors are aware of, none of those inhibitors reached the stage of active clinical development. Either the inhibitor’s potency or pharmacokinetic properties or safety profile or a combination thereof prevented further development of the compounds. More efforts with particular emphasis on optimizing pharmacokinetic and safety properties are needed, potentially by collaborations of academic and industrial research groups with complementary expertise. Furthermore, new warheads reacting with the catalytic cysteine should be exploited to advance the research field in order to make a meaningful impact on society.

About the authors

Maude Giroud

Pharma Research and Early Development pRED, Roche Innovation Center Basel, Medicinal Chemistry, F. Hoffmann-La Roche Ltd.

Email: info@benthamscience.net

Bernd Kuhn

Pharma Research and Early Development pRED, Roche Innovation Center Basel, Medicinal Chemistry, F. Hoffmann-La Roche Ltd.

Email: info@benthamscience.net

Wolfgang Haap

Pharma Research and Early Development pRED, Roche Innovation Center Basel, Medicinal Chemistry, F. Hoffmann-La Roche Ltd.

Author for correspondence.
Email: info@benthamscience.net

References

  1. Neglected tropical diseases. Available from: https://www.who.int/news-room/questions-and-answers/item/neglected-tropical-diseases (Accessed on: 2023- 02-01).
  2. Mora, C.; McKenzie, T.; Gaw, I.M.; Dean, J.M.; von Hammerstein, H.; Knudson, T.A.; Setter, R.O.; Smith, C.Z.; Webster, K.M.; Patz, J.A.; Franklin, E.C. Over half of known human pathogenic diseases can be aggravated by climate change. Nat. Clim. Chang., 2022, 12(9), 869-875. doi: 10.1038/s41558-022-01426-1 PMID: 35968032
  3. Al-Delaimy, A.K. The prospective effects of climate change on neglected tropical diseases in the eastern mediterranean region: A review. Curr. Environ. Health Rep., 2022, 9(2), 315-323. doi: 10.1007/s40572-022-00339-7 PMID: 35286599
  4. Ending the neglect to attain the sustainable development goals: A road map for neglected tropical diseases 2021–2030. Available from: https://www.who.int/publications-detail-redirect/9789240010352 (Accessed on: 2023-02-01).
  5. Sustainable Development Goals ⋅ United Nations Development Programme. UNDP. Available from: https://www.undp.org/sustainable-development-goals (Accessed on: 2023-02-01).
  6. Siqueira-Neto, J.L.; Debnath, A.; McCall, L.I.; Bernatchez, J.A.; Ndao, M.; Reed, S.L.; Rosenthal, P.J. Cysteine proteases in protozoan parasites. PLoS Negl. Trop. Dis., 2018, 12(8), e0006512. doi: 10.1371/journal.pntd.0006512 PMID: 30138453
  7. Rawlings, N.D.; Barrett, A.J.; Thomas, P.D.; Huang, X.; Bateman, A.; Finn, R.D. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res., 2018, 46(D1), D624-D632. doi: 10.1093/nar/gkx1134 PMID: 29145643
  8. Jílková, A.; Horn, M.; Mareš, M. Structural and functional characterization of schistosoma mansoni cathepsin B1. In: Methods in Molecular Biology; Humana Press Inc., 2020; pp. 145-158. doi: 10.1007/978-1-0716-0635-3_12
  9. Caffrey, C.R.; Salter, J.P.; Lucas, K.D.; Khiem, D.; Hsieh, I.; Lim, K.C.; Ruppel, A.; McKerrow, J.H.; Sajid, M. SmCB2, a novel tegumental cathepsin B from adult Schistosoma mansoni. Mol. Biochem. Parasitol., 2002, 121(1), 49-61. doi: 10.1016/S0166-6851(02)00022-1 PMID: 11985862
  10. Sajid, M.; McKerrow, J.H.; Hansell, E.; Mathieu, M.A.; Lucas, K.D.; Hsieh, I.; Greenbaum, D.; Bogyo, M.; Salter, J.P.; Lim, K.C.; Franklin, C.; Kim, J-H.; Caffrey, C.R. Functional expression and characterization of Schistosoma mansoni cathepsin B and its trans-activation by an endogenous asparaginyl endopeptidase. Mol. Biochem. Parasitol., 2003, 131(1), 65-75. doi: 10.1016/S0166-6851(03)00194-4 PMID: 12967713
  11. Jílková, A.; Řezáčová, P.; Lepšík, M.; Horn, M.; Váchová, J.; Fanfrlík, J.; Brynda, J.; McKerrow, J.H.; Caffrey, C.R.; Mareš, M. Structural basis for inhibition of cathepsin B drug target from the human blood fluke, Schistosoma mansoni. J. Biol. Chem., 2011, 286(41), 35770-35781. doi: 10.1074/jbc.M111.271304 PMID: 21832058
  12. Colley, D.G.; Bustinduy, A.L.; Secor, W.E.; King, C.H. Human schistosomiasis. Lancet, 2014, 383(9936), 2253-2264. doi: 10.1016/S0140-6736(13)61949-2 PMID: 24698483
  13. Caffrey, C.R. Chemotherapy of schistosomiasis: Present and future. Curr. Opin. Chem. Biol., 2007, 11(4), 433-439. doi: 10.1016/j.cbpa.2007.05.031 PMID: 17652008
  14. Caffrey, C.R.; Secor, W.E. Schistosomiasis. Curr. Opin. Infect. Dis., 2011, 24(5), 410-417. doi: 10.1097/QCO.0b013e328349156f PMID: 21734570
  15. Thétiot-Laurent, S.A.L.; Boissier, J.; Robert, A.; Meunier, B. Schistosomiasis chemotherapy. Angew. Chem. Int. Ed., 2013, 52(31), 7936-7956. doi: 10.1002/anie.201208390 PMID: 23813602
  16. Caffrey, C.R.; El-Sakkary, N.; Mäder, P.; Krieg, R.; Becker, K.; Schlitzer, M.; Drewry, D.H.; Vennerstrom, J.L.; Grevelding, C.G. Drug discovery and development for schistosomiasis. In: Neglected Tropical Diseases; John Wiley & Sons, Ltd, 2019; pp. 187-225. doi: 10.1002/9783527808656.ch8
  17. Abdulla, M.H.; Lim, K.C.; Sajid, M.; McKerrow, J.H.; Caffrey, C.R. Schistosomiasis mansoni: Novel chemotherapy using a cysteine protease inhibitor. PLoS Med., 2007, 4(1), e14. doi: 10.1371/journal.pmed.0040014 PMID: 17214506
  18. Horn, M.; Jílková, A.; Vondrášek, J.; Marešová, L.; Caffrey, C.R.; Mareš, M. Mapping the pro-peptide of the Schistosoma mansoni cathepsin B1 drug target: modulation of inhibition by heparin and design of mimetic inhibitors. ACS Chem. Biol., 2011, 6(6), 609-617. doi: 10.1021/cb100411v PMID: 21375333
  19. Jílková, A.; Horn, M.; Řezáčová, P.; Marešová, L.; Fajtová, P.; Brynda, J.; Vondrášek, J.; McKerrow, J.H.; Caffrey, C.R.; Mareš, M. Activation route of the Schistosoma mansoni cathepsin B1 drug target: structural map with a glycosaminoglycan switch. Structure, 2014, 22(12), 1786-1798. doi: 10.1016/j.str.2014.09.015 PMID: 25456815
  20. Jílková, A.; Horn, M.; Fanfrlík, J.; Küppers, J.; Pachl, P.; Řezáčová, P.; Lepšík, M.; Fajtová, P.; Rubešová, P.; Chanová, M.; Caffrey, C.R.; Gütschow, M.; Mareš, M. Azanitrile inhibitors of the SmCB1 protease target are lethal to Schistosoma mansoni: Structural and mechanistic insights into chemotype reactivity. ACS Infect. Dis., 2021, 7(1), 189-201. doi: 10.1021/acsinfecdis.0c00644 PMID: 33301315
  21. Jílková, A.; Rubešová, P.; Fanfrlík, J.; Fajtová, P.; Řezáčová, P.; Brynda, J.; Lepšík, M.; Mertlíková-Kaiserová, H.; Emal, C.D.; Renslo, A.R.; Roush, W.R.; Horn, M.; Caffrey, C.R.; Mareš, M. Druggable hot spots in the schistosomiasis cathepsin B1 target identified by functional and binding mode analysis of potent vinyl sulfone inhibitors. ACS Infect. Dis., 2021, 7(5), 1077-1088. doi: 10.1021/acsinfecdis.0c00501 PMID: 33175511
  22. Ward, D.J.; Van de Langemheen, H.; Koehne, E.; Kreidenweiss, A.; Liskamp, R.M.J. Highly tunable thiosulfonates as a novel class of cysteine protease inhibitors with anti- parasitic activity against Schistosoma mansoni. Bioorg. Med. Chem., 2019, 27(13), 2857-2870. doi: 10.1016/j.bmc.2019.05.014 PMID: 31126821
  23. Nakamura, Y.K.; Matsuo, T.; Shimoi, K.; Nakamura, Y.; Tomita, I. S-methyl methanethiosulfonate, bio-antimutagen in homogenates of Cruciferae and Liliaceae vegetables. Biosci. Biotechnol. Biochem., 1996, 60(9), 1439-1443. doi: 10.1271/bbb.60.1439 PMID: 8987591
  24. Rodríguez-Romero, A.; Hernández-Santoyo, A.; del Pozo Yauner, L.; Kornhauser, A.; Fernández-Velasco, D.A. Structure and inactivation of triosephosphate isomerase from Entamoeba histolytica. J. Mol. Biol., 2002, 322(4), 669-675. doi: 10.1016/S0022-2836(02)00809-4 PMID: 12270704
  25. Millian, N.S.; Garrow, T.A. Human betaine-homocysteine methyltransferase is a zinc metalloenzyme. Arch. Biochem. Biophys., 1998, 356(1), 93-98. doi: 10.1006/abbi.1998.0757 PMID: 9681996
  26. Lowther, W.T.; Brot, N.; Weissbach, H.; Honek, J.F.; Matthews, B.W. Thiol–disulfide exchange is involved in the catalytic mechanism of peptide methionine sulfoxide reductase. Proc. Natl. Acad. Sci., 2000, 97(12), 6463-6468. doi: 10.1073/pnas.97.12.6463 PMID: 10841552
  27. Chagas disease. Available from: https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis) (Accessed on: 2023-02-01).
  28. Chagas disease - PAHO/WHO ⋅ Pan American Health Organization. Available from: https://www.paho.org/en/topics/chagas-disease (Accessed on: 2023-02-01).
  29. Symptoms, transmission, and current treatments for Chagas disease ⋅ DNDi. Available from: https://dndi.org/diseases/chagas/facts/ (Accessed on: 2023-02-01).
  30. Engel, J.C.; Doyle, P.S.; Palmer, J.; Hsieh, I.; Bainton, D.F.; McKerrow, J.H. Cysteine protease inhibitors alter Golgi complex ultrastructure and function in Trypanosoma cruzi. J. Cell Sci., 1998, 111(5), 597-606. doi: 10.1242/jcs.111.5.597 PMID: 9454733
  31. McKerrow, J.H. Development of cysteine protease inhibitors as chemotherapy for parasitic diseases: insights on safety, target validation, and mechanism of action. Int. J. Parasitol., 1999, 29(6), 833-837. doi: 10.1016/S0020-7519(99)00044-2 PMID: 10480720
  32. Cazzulo, J.; Stoka, V.; Turk, V. The major cysteine proteinase of Trypanosoma cruzi: A valid target for chemotherapy of Chagas disease. Curr. Pharm. Des., 2001, 7(12), 1143-1156. doi: 10.2174/1381612013397528 PMID: 11472258
  33. Massarico Serafim, R.A.; Gonçalves, J.E.; de Souza, F.P.; de Melo Loureiro, A.P.; Storpirtis, S.; Krogh, R.; Andricopulo, A.D.; Dias, L.C.; Ferreira, E.I. Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity. Eur. J. Med. Chem., 2014, 82, 418-425. doi: 10.1016/j.ejmech.2014.05.077 PMID: 24929292
  34. Ferreira, L.G.; Andricopulo, A.D. Targeting cysteine proteases in trypanosomatid disease drug discovery. Pharmacol. Ther., 2017, 180, 49-61. doi: 10.1016/j.pharmthera.2017.06.004 PMID: 28579388
  35. Doyle, P.S.; Zhou, Y.M.; Hsieh, I.; Greenbaum, D.C.; McKerrow, J.H.; Engel, J.C. The Trypanosoma cruzi protease cruzain mediates immune evasion. PLoS Pathog., 2011, 7(9), e1002139. doi: 10.1371/journal.ppat.1002139 PMID: 21909255
  36. Ndao, M.; Beaulieu, C.; Black, W.C.; Isabel, E.; Vasquez- Camargo, F.; Nath-Chowdhury, M.; Massé, F.; Mellon, C.; Methot, N.; Nicoll-Griffith, D.A. Reversible cysteine protease inhibitors show promise for a Chagas disease cure. Antimicrob. Agents Chemother., 2014, 58(2), 1167-1178. doi: 10.1128/AAC.01855-13 PMID: 24323474
  37. Pauli, I.; Rezende, C.O., Jr; Slafer, B.W.; Dessoy, M.A.; de Souza, M.L.; Ferreira, L.L.G.; Adjanohun, A.L.M.; Ferreira, R.S.; Magalhães, L.G.; Krogh, R.; Michelan-Duarte, S.; Del Pintor, R.V.; da Silva, F.B.R.; Cruz, F.C.; Dias, L.C.; Andricopulo, A.D. Multiparameter optimization of trypanocidal cruzain inhibitors with in vivo activity and favorable pharmacokinetics. Front. Pharmacol., 2022, 12, 774069. doi: 10.3389/fphar.2021.774069 PMID: 35069198
  38. Ferreira, R.S.; Simeonov, A.; Jadhav, A.; Eidam, O.; Mott, B.T.; Keiser, M.J.; McKerrow, J.H.; Maloney, D.J.; Irwin, J.J.; Shoichet, B.K. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J. Med. Chem., 2010, 53(13), 4891-4905. doi: 10.1021/jm100488w PMID: 20540517
  39. Ferreira, R.S.; Dessoy, M.A.; Pauli, I.; Souza, M.L.; Krogh, R.; Sales, A.I.L.; Oliva, G.; Dias, L.C.; Andricopulo, A.D. Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents. J. Med. Chem., 2014, 57(6), 2380-2392. doi: 10.1021/jm401709b PMID: 24533839
  40. Kuhn, B.; Mohr, P.; Stahl, M. Intramolecular hydrogen bonding in medicinal chemistry. J. Med. Chem., 2010, 53(6), 2601-2611. doi: 10.1021/jm100087s PMID: 20175530
  41. Libisch, M.G.; Rego, N.; Robello, C. Transcriptional studies on Trypanosoma cruzi – host cell interactions: A complex puzzle of variables. Front. Cell. Infect. Microbiol., 2021, 11, 692134. doi: 10.3389/fcimb.2021.692134 PMID: 34222052
  42. Neitz, R.J.; Bryant, C.; Chen, S.; Gut, J.; Hugo Caselli, E.; Ponce, S.; Chowdhury, S.; Xu, H.; Arkin, M.R.; Ellman, J.A.; Renslo, A.R. Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease. Bioorg. Med. Chem. Lett., 2015, 25(21), 4834-4837. doi: 10.1016/j.bmcl.2015.06.066 PMID: 26144347
  43. Brak, K.; Kerr, I.D.; Barrett, K.T.; Fuchi, N.; Debnath, M.; Ang, K.; Engel, J.C.; McKerrow, J.H.; Doyle, P.S.; Brinen, L.S.; Ellman, J.A. Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy. J. Med. Chem., 2010, 53(4), 1763-1773. doi: 10.1021/jm901633v PMID: 20088534
  44. Jacobsen, W.; Christians, U.; Benet, L.Z. In vitro evaluation of the disposition of a novel cysteine protease inhibitor. Drug Metab. Dispos., 2000, 28(11), 1343-1351. PMID: 11038163
  45. Tilley, L.; Straimer, J.; Gnädig, N.F.; Ralph, S.A.; Fidock, D.A. Artemisinin action and resistance in Plasmodium falciparum. Trends Parasitol., 2016, 32(9), 682-696. doi: 10.1016/j.pt.2016.05.010 PMID: 27289273
  46. Fact sheet about malaria. Available from: https://www.who.int/news-room/fact-sheets/detail/malaria
  47. Ettari, R.; Bova, F.; Zappalà, M.; Grasso, S.; Micale, N. Falcipain-2 inhibitors. Med. Res. Rev., 2010, 30(1), 136-167. doi: 10.1002/med.20163 PMID: 19526594
  48. Bekono, B.D.; Ntie-Kang, F.; Owono Owono, L.C.; Megnassan, E. Targeting cysteine proteases from Plasmodium falciparum: A general overview, rational drug design and computational approaches for drug discovery. Curr. Drug Targets, 2018, 19(5), 501-526. doi: 10.2174/1389450117666161221122432 PMID: 28003005
  49. Chen, W.; Huang, Z.; Wang, W.; Mao, F.; Guan, L.; Tang, Y.; Jiang, H.; Li, J.; Huang, J.; Jiang, L.; Zhu, J. Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely. Bioorg. Med. Chem., 2017, 25(24), 6467-6478. doi: 10.1016/j.bmc.2017.10.017 PMID: 29111368
  50. Stoye, A.; Juillard, A.; Tang, A.H.; Legac, J.; Gut, J.; White, K.L.; Charman, S.A.; Rosenthal, P.J.; Grau, G.E.R.; Hunt, N.H.; Payne, R.J. Falcipain inhibitors based on the natural product gallinamide a are potent in vitro and in vivo antimalarials. J. Med. Chem., 2019, 62(11), 5562-5578. doi: 10.1021/acs.jmedchem.9b00504 PMID: 31062592
  51. Gresty, K.J.; Gray, K.A.; Bobogare, A.; Wini, L.; Taleo, G.; Hii, J.; Cheng, Q.; Waters, N.C. Genetic mutations in Plasmodium falciparum and Plasmodium vivax dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in Vanuatu and Solomon Islands prior to the introduction of artemisinin combination therapy. Malar. J., 2014, 13(1), 402. doi: 10.1186/1475-2875-13-402 PMID: 25311473
  52. Metzger, V.T.; Eun, C.; Kekenes-Huskey, P.M.; Huber, G.; McCammon, J.A. Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling. Biophys. J., 2014, 107(10), 2394-2402. doi: 10.1016/j.bpj.2014.09.039 PMID: 25418308
  53. Barnett, D.S.; Guy, R.K. Antimalarials in development in 2014. Chem. Rev., 2014, 114(22), 11221-11241. doi: 10.1021/cr500543f PMID: 25340626
  54. Lamb, K.M.; G-Dayanandan, N.; Wright, D.L.; Anderson, A.C. Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase. Biochemistry, 2013, 52(41), 7318-7326. doi: 10.1021/bi400852h PMID: 24053334
  55. Huang, H.; Lu, W.; Li, X.; Cong, X.; Ma, H.; Liu, X.; Zhang, Y.; Che, P.; Ma, R.; Li, H.; Shen, X.; Jiang, H.; Huang, J.; Zhu, J. Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent. Bioorg. Med. Chem. Lett., 2012, 22(2), 958-962. doi: 10.1016/j.bmcl.2011.12.011 PMID: 22192590
  56. Conroy, T.; Guo, J.T.; Elias, N.; Cergol, K.M.; Gut, J.; Legac, J.; Khatoon, L.; Liu, Y.; McGowan, S.; Rosenthal, P.J.; Hunt, N.H.; Payne, R.J. Synthesis of gallinamide A analogues as potent falcipain inhibitors and antimalarials. J. Med. Chem., 2014, 57(24), 10557-10563. doi: 10.1021/jm501439w PMID: 25412465
  57. Brun, R.; Blum, J.; Chappuis, F.; Burri, C. Human African trypanosomiasis. Lancet, 2010, 375(9709), 148-159. doi: 10.1016/S0140-6736(09)60829-1 PMID: 19833383
  58. Feasey, N.; Wansbrough-Jones, M.; Mabey, D.C.W.; Solomon, A.W. Neglected tropical diseases. Br. Med. Bull., 2010, 93(1), 179-200. doi: 10.1093/bmb/ldp046 PMID: 20007668
  59. Malvy, D.; Chappuis, F. Sleeping sickness. Clin. Microbiol. Infect., 2011, 17(7), 986-995. doi: 10.1111/j.1469-0691.2011.03536.x PMID: 21722252
  60. Priotto, G.; Kasparian, S.; Mutombo, W.; Ngouama, D.; Ghorashian, S.; Arnold, U.; Ghabri, S.; Baudin, E.; Buard, V.; Kazadi-Kyanza, S.; Ilunga, M.; Mutangala, W.; Pohlig, G.; Schmid, C.; Karunakara, U.; Torreele, E.; Kande, V. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, randomised, phase III, non-inferiority trial. Lancet, 2009, 374(9683), 56-64. doi: 10.1016/S0140-6736(09)61117-X PMID: 19559476
  61. Bisser, S.; N’Siesi, F.X.; Lejon, V.; Preux, P.M.; Van Nieuwenhove, S.; Miaka Mia Bilenge, C.; Büscher, P. Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J. Infect. Dis., 2007, 195(3), 322-329. doi: 10.1086/510534 PMID: 17205469
  62. Delespaux, V.; Dekoning, H. Drugs and drug resistance in African trypanosomiasis. Drug Resist. Updat., 2007, 10(1-2), 30-50. doi: 10.1016/j.drup.2007.02.004 PMID: 17409013
  63. DNDi – Best science for the most neglected. Available from: https://dndi.org/(Accessed on: 2023-02-01).
  64. Mesu, V.K.B.K.; Kalonji, W.M.; Bardonneau, C.; Mordt, O.V.; Blesson, S.; Simon, F.; Delhomme, S.; Bernhard, S.; Kuziena, W.; Lubaki, J.P.F.; Vuvu, S.L.; Ngima, P.N.; Mbembo, H.M.; Ilunga, M.; Bonama, A.K.; Heradi, J.A.; Solomo, J.L.L.; Mandula, G.; Badibabi, L.K.; Dama, F.R.; Lukula, P.K.; Tete, D.N.; Lumbala, C.; Scherrer, B.; Strub- Wourgaft, N.; Tarral, A. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: A pivotal multicentre, randomised, non-inferiority trial. Lancet, 2018, 391(10116), 144-154. doi: 10.1016/S0140-6736(17)32758-7 PMID: 29113731
  65. Fexinidazole for T.b. rhodesiense ⋅ DNDi. Available from: https://dndi.org/research-development/portfolio/fexinidazole-tb-rhodesiense/ (Accessed on: 2023-02-01).
  66. Betu Kumeso, V.K.; Kalonji, W.M.; Rembry, S.; Valverde, M.O.; Ngolo, T.D.; Prêtre, A.; Delhomme, S.; Ilunga, W.K.M.; Camara, M.; Catusse, J.; Schneitter, S.; Nusbaumer, M.; Mwamba, M.E.; Mahenzi, M.H.; Makaya, M.J.; Layba, C.M.; Akwaso, M.F.; Kaninda, B.L.; Kasongo, B.A.; Kavunga, L.P.; Mutanda, K.S.; Mariero, P.P.; Mokilifi, N.R.; Embana, M.H.; Asuka, A.N.A.; Kobo, M.V.; Mulenge, N.E.; Fifi, N.B.A.; Scherrer, B.; Strub- Wourgaft, N.; Tarral, A. Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: A multicentre, open-label, single-arm, phase 2/3 trial. Lancet Infect. Dis., 2023, 23(4), 463-470. doi: 10.1016/S1473-3099(22)00660-0 PMID: 36460027
  67. Ettari, R.; Previti, S.; Tamborini, L.; Cullia, G.; Grasso, S.; Zappalà, M. The inhibition of cysteine proteases rhodesain and TbCatB: A valuable approach to treat human African trypanosomiasis. Mini Rev. Med. Chem., 2016, 16(17), 1374-1391. doi: 10.2174/1389557515666160509125243 PMID: 27156518
  68. Caffrey, C.R.; Hansell, E.; Lucas, K.D.; Brinen, L.S.; Alvarez Hernandez, A.; Cheng, J.; Gwaltney, S.L., II; Roush, W.R.; Stierhof, Y.D.; Bogyo, M.; Steverding, D.; McKerrow, J.H. Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Mol. Biochem. Parasitol., 2001, 118(1), 61-73. doi: 10.1016/S0166-6851(01)00368-1 PMID: 11704274
  69. Davidbarry, J.; McCulloch, R. Antigenic variation in trypanosomes: Enhanced phenotypic variation in a eukaryotic parasite. Adv. Parasitol., 2001, 49, 1-70. doi: 10.1016/S0065-308X(01)49037-3 PMID: 11461029
  70. Overath, P.; Chaudhri, M.; Steverding, D.; Ziegelbauer, K. Invariant surface proteins in bloodstream forms of Trypanosoma brucei. Parasitol. Today, 1994, 10(2), 53-58. doi: 10.1016/0169-4758(94)90393-X PMID: 15275499
  71. Lonsdale-Eccles, J.D.; Grab, D.J. Trypanosome hydrolases and the blood–brain barrier. Trends Parasitol., 2002, 18(1), 17-19. doi: 10.1016/S1471-4922(01)02120-1 PMID: 11850009
  72. Abdulla, M.H.; O’Brien, T.; Mackey, Z.B.; Sajid, M.; Grab, D.J.; McKerrow, J.H. RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model. PLoS Negl. Trop. Dis., 2008, 2(9), e298. doi: 10.1371/journal.pntd.0000298 PMID: 18820745
  73. Steverding, D.; Sexton, D.W.; Wang, X.; Gehrke, S.S.; Wagner, G.K.; Caffrey, C.R. Trypanosoma brucei: Chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int. J. Parasitol., 2012, 42(5), 481-488. doi: 10.1016/j.ijpara.2012.03.009 PMID: 22549023
  74. Kerr, I.D.; Lee, J.H.; Farady, C.J.; Marion, R.; Rickert, M.; Sajid, M.; Pandey, K.C.; Caffrey, C.R.; Legac, J.; Hansell, E.; McKerrow, J.H.; Craik, C.S.; Rosenthal, P.J.; Brinen, L.S. Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J. Biol. Chem., 2009, 284(38), 25697-25703. doi: 10.1074/jbc.M109.014340 PMID: 19620707
  75. Kerr, I.D.; Wu, P.; Marion-Tsukamaki, R.; Mackey, Z.B.; Brinen, L.S. Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei. PLoS Negl. Trop. Dis., 2010, 4(6), e701. doi: 10.1371/journal.pntd.0000701 PMID: 20544024
  76. Giroud, M.; Kuhn, B.; Saint-Auret, S.; Kuratli, C.; Martin, R.E.; Schuler, F.; Diederich, F.; Kaiser, M.; Brun, R.; Schirmeister, T.; Haap, W. 2 H-1,2,3-triazole-based dipeptidyl nitriles: Potent, selective, and trypanocidal rhodesain inhibitors by structure-based design. J. Med. Chem., 2018, 61(8), 3370-3388. doi: 10.1021/acs.jmedchem.7b01870 PMID: 29590751
  77. Giroud, M.; Dietzel, U.; Anselm, L.; Banner, D.; Kuglstatter, A.; Benz, J.; Blanc, J.B.; Gaufreteau, D.; Liu, H.; Lin, X.; Stich, A.; Kuhn, B.; Schuler, F.; Kaiser, M.; Brun, R.; Schirmeister, T.; Kisker, C.; Diederich, F.; Haap, W. Repurposing a library of human cathepsin L ligands: Identification of macrocyclic lactams as potent rhodesain and Trypanosoma brucei inhibitors. J. Med. Chem., 2018, 61(8), 3350-3369. doi: 10.1021/acs.jmedchem.7b01869 PMID: 29590750
  78. Eliel, E.L.; Wilen, S.H.; Mander, L.N. Chirality in molecules devoid of chiral centers. University of Pittsburgh, 1994.
  79. LaPlante, S.R.; Forgione, P.; Boucher, C.; Coulombe, R.; Gillard, J.; Hucke, O.; Jakalian, A.; Joly, M.A.; Kukolj, G.; Lemke, C.; McCollum, R.; Titolo, S.; Beaulieu, P.L.; Stammers, T. Enantiomeric atropisomers inhibit HCV polymerase and/or HIV matrix: characterizing hindered bond rotations and target selectivity. J. Med. Chem., 2014, 57(5), 1944-1951. doi: 10.1021/jm401202a PMID: 24024973
  80. Target product profile for sleeping sickness ⋅ DNDi. Available from: https://dndi.org/diseases/sleeping-sickness/target-product-profile/ (Accessed on: 2023-02-01).
  81. Jung, S.; Fuchs, N.; Johe, P.; Wagner, A.; Diehl, E.; Yuliani, T.; Zimmer, C.; Barthels, F.; Zimmermann, R.A.; Klein, P.; Waigel, W.; Meyr, J.; Opatz, T.; Tenzer, S.; Distler, U.; Räder, H.J.; Kersten, C.; Engels, B.; Hellmich, U.A.; Klein, J.; Schirmeister, T. Fluorovinylsulfones and -sulfonates as potent covalent reversible inhibitors of the trypanosomal cysteine protease rhodesain: Structure–activity relationship, inhibition mechanism, metabolism, and in vivo studies. J. Med. Chem., 2021, 64(16), 12322-12358. doi: 10.1021/acs.jmedchem.1c01002 PMID: 34378914
  82. Lee, C.U.; Grossmann, T.N. Reversible covalent inhibition of a protein target. Angew. Chem. Int. Ed., 2012, 51(35), 8699-8700. doi: 10.1002/anie.201203341 PMID: 22806944
  83. Lammert, C.; Einarsson, S.; Saha, C.; Niklasson, A.; Bjornsson, E.; Chalasani, N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: Search for signals. Hepatology, 2008, 47(6), 2003-2009. doi: 10.1002/hep.22272 PMID: 18454504
  84. Kalgutkar, A.S.; Dalvie, D.K. Drug discovery for a new generation of covalent drugs. Expert Opin. Drug Discov., 2012, 7(7), 561-581. doi: 10.1517/17460441.2012.688744 PMID: 22607458
  85. Jung, S.; Fuchs, N.; Grathwol, C.; Hellmich, U.A.; Wagner, A.; Diehl, E.; Willmes, T.; Sotriffer, C.; Schirmeister, T. New peptidomimetic rhodesain inhibitors with improved selectivity towards human cathepsins. Eur. J. Med. Chem., 2022, 238, 114460. doi: 10.1016/j.ejmech.2022.114460 PMID: 35597010
  86. Boike, L.; Henning, N.J.; Nomura, D.K. Advances in covalent drug discovery. Nat. Rev. Drug Discov., 2022, 21(12), 881-898. doi: 10.1038/s41573-022-00542-z PMID: 36008483
  87. Serafim, R.A.M.; Haarer, L.; Pedreira, J.G.B.; Gehringer, M. Covalent chemical probes for protein kinases. Curr. Opin. Chem. Biol., 2023, 3, 100040. doi: 10.1016/j.crchbi.2022.100040
  88. De Vita, E. 10 years into the resurgence of covalent drugs. Future Med. Chem., 2021, 13(2), 193-210. doi: 10.4155/fmc-2020-0236 PMID: 33275063

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