Nucleoside analogues for the treatment of animal trypanosomiasis

Mabille, Dorien; Ilbeigi, Kayhan; Hendrickx, Sarah; Ungogo, Marzuq A.; Hulpia, Fabian; Chen, Lin; Maes, Louis; Koning, Harry P. de; Calenbergh, Serge Van; Caljon, Guy

doi:10.1016/j.ijpddr.2022.05.001

Cited by 13 publications

(19 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has also long been known that protozoan nucleoside transporters mediate the uptake of cytotoxic nucleoside analogues including formycin B and tubercidin used in this study but also, e.g., adenosine arabinoside in T. gondii [ 18 ] and cordycepin in T. brucei [ 10 , 56 ]. Very recently, a class of 7-substituted,7-deaza analogues of adenosine and inosine have shown great promise against multiple protozoan pathogens [ 9 , 12 , 13 , 14 , 57 , 58 ], which is clearly mediated by uptake through nucleoside transporters [ 8 , 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…A well-studied example is the role of the TbAT1/P2 aminopurine transporter of T. brucei in the uptake of melaminophenyl arsenicals and diamidines [ 5 , 6 , 7 ]. In recent years, purine antimetabolites have been shown to be among the most effective classes of antiprotozoal compounds, with promising activities against Trypanosoma brucei [ 8 , 9 , 10 , 11 ], T. congolense [ 12 ], T. cruzi [ 13 ], Trichomonas vaginalis [ 14 ], and Leishmania spp. [ 15 ], among others, placing further emphasis on the pharmacological importance of nucleoside carriers.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters

Aldfer

AlSiari

Elati

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

The study of transporters is highly challenging, as they cannot be isolated or studied in suspension, requiring a cellular or vesicular system, and, when mediated by more than one carrier, difficult to interpret. Nucleoside analogues are important drug candidates, and all protozoan pathogens express multiple equilibrative nucleoside transporter (ENT) genes. We have therefore developed a system for the routine expression of nucleoside transporters, using CRISPR/cas9 to delete both copies of all three nucleoside transporters from Leishmania mexicana (ΔNT1.1/1.2/2 (SUPKO)). SUPKO grew at the same rate as the parental strain and displayed no apparent deficiencies, owing to the cells’ ability to synthesize pyrimidines, and the expression of the LmexNT3 purine nucleobase transporter. Nucleoside transport was barely measurable in SUPKO, but reintroduction of L. mexicana NT1.1, NT1.2, and NT2 restored uptake. Thus, SUPKO provides an ideal null background for the expression and characterization of single ENT transporter genes in isolation. Similarly, an LmexNT3-KO strain provides a null background for transport of purine nucleobases and was used for the functional characterization of T. cruzi NB2, which was determined to be adenine-specific. A 5-fluorouracil-resistant strain (Lmex5FURes) displayed null transport for uracil and 5FU, and was used to express the Aspergillus nidulans uracil transporter FurD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters

Aldfer

AlSiari

Elati

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…5 Yet, the benefits of having an active trypanocidal molecule that can be efficiently internalized via P1-like transporters goes beyond likely overcoming the rise of drug resistance because of the loss of transporter functionality and also include their chemotherapeutical potential against several Trypanosoma species. 7 Of note, an orthologue of P1 from T. congolense (TcoAT1) has been characterized and shown to be functionally similar to its T. brucei counterpart. 8 As such, TcoAT1 is not involved in diminazene uptake.…”

mentioning

confidence: 99%

“…Noteworthy, 3′-deoxytbercidin and several of its analogues are broadly active against animal trypanosomes 7 and in vivo treatment with 3′-deoxytubercidin cured chronic T. brucei 13 and acute T. congolense 7 infections in mice. These findings seem to have inflated the interest in tubercidin to improve its trypanocidal potential and reduce its toxicity to mammals.…”

mentioning

confidence: 99%

“…However, the required cooperativeness between the H-bonds formed between the transporter and its substrates generally hinders the ability of P1 to transport trypanocidal drugs . Yet, the benefits of having an active trypanocidal molecule that can be efficiently internalized via P1-like transporters goes beyond likely overcoming the rise of drug resistance because of the loss of transporter functionality and also include their chemotherapeutical potential against several Trypanosoma species …”

mentioning

confidence: 99%

See 1 more Smart Citation

Purine Transporters as Efficient Carriers for Anti-kinetoplastid Molecules: 3′-Deoxytubercidin versus Trypanosomes

Campagnaro

2022

ACS Infect. Dis.

View full text Add to dashboard Cite

After a growing interest in the function of purine transporters in protozoa during the 1990s and early 2000s, the area experienced a lull phase. Recently, however, the potential of tubercidin derivatives, particularly 3′-deoxytubercidin, to cure Trypanosoma brucei infection seems to have started a new wave of interest in the subject, with a large number of newly designed compounds and extensive in vitro testing against T. brucei, Trypanosoma cruzi, and Leishmania spp. Understanding the biochemical properties of purine transporters and using them as drug carriers seem to be emerging once again as a valuable tactic in the fight against neglected diseases.

show abstract

Novel quinoline derivatives with broad‐spectrum antiprotozoal activities

Hartman,

Dube,

Legoabe

et al. 2024

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half‐maximal effective concentration (EC50) values of 0.68, 0.8, and 0.19 µM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages (∼100‐fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC50 values of 1.4 and 0.4 µM, respectively.

show abstract

Nucleoside analogues for the treatment of animal trypanosomiasis

Cited by 13 publications

References 43 publications

Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters

Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters

Purine Transporters as Efficient Carriers for Anti-kinetoplastid Molecules: 3′-Deoxytubercidin versus Trypanosomes

Novel quinoline derivatives with broad‐spectrum antiprotozoal activities

Contact Info

Product

Resources

About