Login Register Cart 0
Perspective

Proteasome as a Drug Target in Trypanosomatid Diseases

Author(s): Mariana Luiza Silva, Kaio Maciel de Santiago-Silva, Marciéli Fabris, Priscila Goes Camargo and Marcelle de Lima Ferreira Bispo*

Volume 24, Issue 10, 2023

Published on: 20 July, 2023

Page: [781 - 789] Pages: 9

DOI: 10.2174/1389450124666230719104147

Abstract

Some diseases caused by trypanosomatid parasites, like Leishmaniasis, Chagas Disease, and Human African Trypanosomiasis (HTA), are challenging to manage, mainly concerning pharmacological therapy because they are associated with vulnerable populations. Unfortunately, there is a lack of significant investments in the search for new drugs. Therefore, one of the strategies to aid the discovery of new drugs is to identify and inhibit molecular targets essential to the parasite's survival, such as the proteasome, which degrades most proteins in the parasite cells. Our study has presented several proteasome inhibitors with various pharmacophoric cores, and two of them, 5, and 13, have stood out in the clinical phase of treatment for leishmaniasis.

Keywords: Trypanosomatid, Neglected tropical disease, Leishmaniasis, Chagas, Sleeping sickness, HTA.

« Previous Next »
[1]
Leishmaniasis, World Heal. Organ 2022.
[2]
Burza S, Croft SL, Boelaert M. Leishmaniasis. Lancet 2018; 392(10151): 951-70.
[http://dx.doi.org/10.1016/S0140-6736(18)31204-2] [PMID: 30126638]
[3]
WHO. Chagas disease (American trypanosomiasis), World Heal Organ 2022.
[4]
Chatelain E. Chagas disease drug discovery: Toward a new era. SLAS Discov 2015; 20(1): 22-35.
[http://dx.doi.org/10.1177/1087057114550585] [PMID: 25245987]
[5]
Lopes RD, Gimpelewicz C, McMurray JJV. Chagas disease: Still a neglected emergency? Lancet 2020; 395(10230): 1113-4.
[http://dx.doi.org/10.1016/S0140-6736(20)30171-9] [PMID: 32247391]
[6]
Sutherland CS, Yukich J, Goeree R, Tediosi F. A literature review of economic evaluations for a neglected tropical disease: Human African trypanosomiasis (“sleeping sickness”). PLoS Negl Trop Dis 2015; 9(2): e0003397.
[http://dx.doi.org/10.1371/journal.pntd.0003397] [PMID: 25654605]
[7]
Du X, Hansell E, Engel JC, Caffrey CR, Cohen FE, McKerrow JH. Aryl ureas represent a new class of anti-trypanosomal agents. Chem Biol 2000; 7(9): 733-42.
[http://dx.doi.org/10.1016/S1074-5521(00)00018-1] [PMID: 10980453]
[8]
Büscher P, Cecchi G, Jamonneau V, Priotto G. Human African trypanosomiasis. Lancet 2017; 390(10110): 2397-409.
[http://dx.doi.org/10.1016/S0140-6736(17)31510-6] [PMID: 28673422]
[9]
WHO. Model lists of essential medicines, world heal. Organ 2022.
[10]
Pedrique B, Strub-Wourgaft N, Some C, et al. The drug and vaccine landscape for neglected diseases (2000–11): A systematic assessment. Lancet Glob Health 2013; 1(6): e371-9.
[http://dx.doi.org/10.1016/S2214-109X(13)70078-0] [PMID: 25104602]
[11]
Bijlmakers MJ. Ubiquitination and the proteasome as drug targets in trypanosomatid diseases. Front Chem 2021; 8: 630888.
[http://dx.doi.org/10.3389/fchem.2020.630888] [PMID: 33732684]
[12]
Burge RJ, Damianou A, Wilkinson AJ, Rodenko B, Mottram JC. Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex. PLoS Pathog 2020; 16(10): e1008784.
[http://dx.doi.org/10.1371/journal.ppat.1008784] [PMID: 33108402]
[13]
Khare S, Nagle AS, Biggart A, et al. Proteasome inhibition for treatment of leishmaniasis, chagas disease and sleeping sickness. Nature 2016; 537(7619): 229-33.
[http://dx.doi.org/10.1038/nature19339] [PMID: 27501246]
[14]
Nagle A, Biggart A, Be C, et al. Discovery and characterization of clinical candidate lxe408 as a kinetoplastid-selective proteasome inhibitor for the treatment of leishmaniases. J Med Chem 2020; 63(19): 10773-81.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00499] [PMID: 32667203]
[15]
Wyllie S, Brand S, Thomas M, et al. Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition. Proc Natl Acad Sci 2019; 116(19): 9318-23.
[http://dx.doi.org/10.1073/pnas.1820175116] [PMID: 30962368]
[16]
Thomas M, Brand S, De Rycker M, et al. Scaffold-hopping strategy on a series of proteasome inhibitors led to a preclinical candidate for the treatment of visceral leishmaniasis. J Med Chem 2021; 64(9): 5905-30.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00047] [PMID: 33904304]
[17]
Zmuda F, Sastry L, Shepherd SM, et al. Identification of novel trypanosoma cruzi proteasome inhibitors using a luminescence-based high-throughput screening assay. Antimicrob Agents Chemother 2019; 63(9): e00309-19.
[http://dx.doi.org/10.1128/AAC.00309-19] [PMID: 31307977]
[18]
Nagendar P, Gillespie JR, Herbst ZM, et al. Triazolopyrimidines and imidazopyridines: Structure–activity relationships and in vivo efficacy for trypanosomiasis. ACS Med Chem Lett 2019; 10(1): 105-10.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00498] [PMID: 30655955]
[19]
Tatipaka HB, Gillespie JR, Chatterjee AK, et al. Substituted 2-phenylimidazopyridines: A new class of drug leads for human African trypanosomiasis. J Med Chem 2014; 57(3): 828-35.
[http://dx.doi.org/10.1021/jm401178t] [PMID: 24354316]
[20]
Lima ML, Tulloch LB, Corpas-Lopez V, et al. Identification of a proteasome-targeting arylsulfonamide with potential for the treatment of chagas’ disease. Antimicrob Agents Chemother 2022; 66(1): e01535-21.
[http://dx.doi.org/10.1128/AAC.01535-21] [PMID: 34606338]

Rights & Permissions Print Cite
Article Metrics
33
2
© 2024 Bentham Science Publishers | Privacy Policy