Exploring the latest breakthroughs in rhodesain inhibitors for African trypanosomiasis

World Health Organization. Neglected tropical diseases. www.who.int/health-topics/neglected-tropical-diseases#tab=tab_2 (Accessed Mar 16, 2023).

Büscher P, Cecchi G, Jamonneau V, Priotto G. Human African Trypanosomiasis. Lancet. 2017;390:2397–409.

Article  PubMed  Google Scholar 

Gao JM, Qian ZY, Hide G, Lai DH, Lun ZR, Wu ZD. Human African Trypanosomiasis: the current situation in endemic regions and the risks for non-endemic regions from imported cases. Parasitology. 2020;147:922–31.

Article  PubMed  PubMed Central  Google Scholar 

Simarro PP, Cecchi G, Paone M, Franco JR, Diarra A, Ruiz JA, et al. The Atlas of Human African Trypanosomiasis: a contribution to global mapping of neglected tropical diseases. Int J Health Geogr 2010;9:57.

Article  PubMed  PubMed Central  Google Scholar 

Kennedy PGE. Update on Human African Trypanosomiasis (Sleeping Sickness). J Neurol 2019;266:2334–7.

Article  CAS  PubMed  Google Scholar 

Fairlamb AH, Bowman IBR. Trypanosoma brucei: suramin and other trypanocidal compounds’ effects on sn-glycerol-3-phosphate oxidase. Exp Parasitol 1977;43:353–61.

Article  CAS  PubMed  Google Scholar 

Fairlamb AH, Bowman IB. Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo. Mol Biochem Parasitol 1980;1:315–33.

Article  CAS  PubMed  Google Scholar 

Willson M, Callens M, Kuntz DA, Perié J, Opperdoes FR. Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei. Mol Biochem Parasitol 1993;59:201–10.

Article  CAS  PubMed  Google Scholar 

Morty RE, Troeberg L, Pike RN, Jones R, Nickel P, Lonsdale-Eccles JD, et al. A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin. FEBS Lett. 1998;433:251–6.

Article  CAS  PubMed  Google Scholar 

Zimmermann S, Hall L, Riley S, Sørensen J, Amaro RE, Schnaufer A. A novel high-throughput activity assay for the Trypanosoma brucei editosome enzyme REL1 and other RNA ligases. Nucleic Acids Res. 2016;44:e24.

Article  PubMed  Google Scholar 

Albisetti A, Hälg S, Zoltner M, Mäser P, Wiedemar N. Suramin action in African trypanosomes involves a RuvB-like DNA helicase. Int J Parasitol Drugs Drug Resist. 2023;23:44–53.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shapiro TA, Englund PT. Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proc Natl Acad Sci USA. 1990;87:950–4.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Baker N, Koning HP, Mäser P, Horn D. Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story. Trends Parasitol. 2013;29:110–8.

Article  CAS  PubMed  Google Scholar 

Fairlamb AH, Henderson GB, Cerami A. Trypanothione is the primary target for arsenical drugs against African trypanosomes. Proc Natl Acad Sci USA. 1989;86:2607–11.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Vincent IM, Creek D, Watson DG, Kamleh MA, Woods DJ, Wong PE, et al. A molecular mechanism for eflornithine resistance in African trypanosomes. PLoS Pathog. 2010;6:e1001204.

Article  PubMed  PubMed Central  Google Scholar 

Fairlamb AH, Henderson GB, Bacchi CJ, Cerami A. In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in bloodstream forms of Trypanosoma brucei. Mol Biochem Parasitol. 1987;24:185–91.

Article  CAS  PubMed  Google Scholar 

Poulin R, Lu L, Ackermann B, Bey P, Pegg AE. Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J Biol Chem. 1992;267:150–8.

Article  CAS  PubMed  Google Scholar 

Keating J, Yukich JO, Sutherland CS, Woods G, Tediosi F. Human African Trypanosomiasis prevention, treatment and control costs: a systematic review. Acta Trop. 2015;150:4–13.

Article  PubMed  Google Scholar 

US National Library of medicine. Clinical trials home page. Bethesda (MD); National Library of Medicine. clinicaltrials.gov/ (Accessed Mar 13, 2023).

Mesu VKBK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, et al. Oral fexinidazole for late-stage African trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018;391:144–54.

Article  CAS  PubMed  Google Scholar 

MEROPS, the peptidase database. www.ebi.ac.uk/merops/ (Accessed Mar 14, 2023).

Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD. 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:D624–D632.

Article  CAS  PubMed  Google Scholar 

Steverding D, Caffrey CR. Should the enzyme name ‘Rhodesain’ be discontinued? Mol Biochem Parasitol. 2021;245:111395.

Article  CAS  PubMed  Google Scholar 

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;16:1374–91.

Article  CAS  PubMed  Google Scholar 

Lonsdale-Eccles JD, Grab DJ. Trypanosome hydrolases and the blood-brain barrier. Trends Parasitol. 2002;18:17–19.

Article  CAS  PubMed  Google Scholar 

Nikolskaia OV, Lima APCDA, Kim YV, Lonsdale-Eccles JD, Fukuma T, Scharfstein J, et al. Blood-brain barrier traversal by African Trypanosomes requires calcium signaling induced by parasite cysteine protease. J Clin Invest. 2006;116:2739–47.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Grab DJ, Garcia-Garcia JC, Nikolskaia OV, Kim YV, Brown A, Pardo CA, et al. Protease activated receptor signaling is required for African trypanosome traversal of human brain microvascular endothelial cells. PLoS Negl Trop Dis. 2009;3:e479.

Article  PubMed  PubMed Central  Google Scholar 

Steverding D, Sexton DW, Wang X, Gehrke SS, Wagner GK, Caffrey CR. Trypanosoma Brucei: chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int J Parasitol. 2012;42:481–8.

Article  CAS  PubMed  Google Scholar 

Ettari R, Tamborini L, Angelo IC, Micale N, Pinto A, Micheli C, et al. Inhibition of Rhodesain as a novel therapeutic modality for human African Trypanosomiasis. J Med Chem. 2013;56:5637–58.

Article  CAS  PubMed  Google Scholar 

Johé P, Jaenicke E, Neuweiler H, Schirmeister T, Kersten C, Hellmich UA. Structure, interdomain dynamics, and PH-dependent autoactivation of pro-Rhodesain, the main lysosomal cysteine protease from African Trypanosomes. J Biol Chem. 2021;296:100565.

Article  PubMed  PubMed Central  Google Scholar 

Nascimento IJ, dos S, Aquino TM, de; Silva-Júnior EF. da. Cruzain and Rhodesain inhibitors: last decade of advances in seeking for new compounds against American and African Trypanosomiases. Curr Top Med Chem. 2021;21:1871–99.

Article  Google Scholar 

Alvarez VE, Iribarren PA, Niemirowicz GT, Cazzulo JJ. Update on relevant trypanosome peptidases: validated targets and future challenges. Biochim Biophys Acta - Proteins Proteom. 2021;1869:140577.

Article  CAS  PubMed  Google Scholar 

Petri GL, Di Martino S, De Rosa M. Peptidomimetics: an overview of recent medicinal chemistry efforts toward the discovery of novel small. Mol Inhib J Med Chem. 2022;65:7438–75.

Article  Google Scholar 

El-Faham A, de la Torre BG, Albericio F. Latest advances on synthesis, purification, and characterization of peptides and their applications. Appl Sci. 2021;11:5593.

Article  CAS  Google Scholar 

Palmer JT, Rasnick D, Klaus JL, Bromme D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J Med Chem. 1995;38:3193–6.

Article  CAS  PubMed  Google Scholar 

Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, et al. Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J Biol Chem 2009;284:25697–703.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Royo S, Rodríguez S, Schirmeister T, Kesselring J, Kaiser M, González FV. Dipeptidyl enoates as potent rhodesain inhibitors that display a dual mode of action. ChemMedChem. 2015;10:1484–7.

Article  CAS  PubMed  Google Scholar 

Royo S, Schirmeister T, Kaiser M, Jung S, Rodríguez S, Bautista JM, et al. Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates. Bioorg Med Chem. 2018;26:4624–34.

Article  CAS  PubMed 

Comments (0)

No login
gif