Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)

Akama, Tsutomu; Zhang, Yongkang; Freund, Yvonne R.; Berry, Pamela; Lee, Joanne; Easom, Eric E.; Jacobs, Robert T.; Plattner, Jacob J.; Witty, Michael; Peter, Rose; Rowan, T.G.; Gillingwater, Kirsten; Brun, Reto; Nare, Bakela; Mercer, Luke; Xu, Musheng; Wang, Jiangong; Liang, Hao

doi:10.1016/j.bmcl.2017.11.028

Cited by 43 publications

(37 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…rhodesiense, and African animal trypanosomiasis (AAT) due to T. congolense and T. vivax. 36,37 . Members of this class have also shown favorable safety profiles, which enhanced the status of AN7973 for the repositioning strategy of this program.…”

Section: Resultsmentioning

confidence: 99%

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Lunde¹,

Stebbins²,

Jumani³

et al. 2019

Nat Commun

Self Cite

View full text Add to dashboard Cite

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis . It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Lunde¹,

Stebbins²,

Jumani³

et al. 2019

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Nevertheless, some trends with respect to molecules with the same scaffolds can be noted. For example the two compounds AN15368 and AN11736 are both L-valinate amide benzoxaboroles [24] and both showed very little Y structure inhibition (Figs. 6 & 8).…”

Section: Discussionmentioning

confidence: 99%

“…Testing of T. congolense in vitro (72 hrs) and T. vivax ex vivo (48 hrs) assays were done as described in [65]. Testing of T. congolense and T. vivax in vivo in mice was done as described in [24]. All in vivo mouse experiments were carried out in accordance with the strict regulations set out by the Swiss Federal Veterinary Office, under the ethical approval of the Canton of Basel City, under license number #2813.…”

Section: Compound Efficacy Studies For T Congolense and T Vivaxmentioning

confidence: 99%

The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing

Begolo

Vincent

Giordani

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Kinetoplastid parasites -trypanosomes and leishmanias -infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. Their targets in trypanosomes were hitherto unknown. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate and reduced levels of mRNA, and accumulation of peri-nuclear granules which are typical for splicing inhibition. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, these results indicate that mRNA processing is the primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing. The EC 50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action, and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition, and resistance after CPSF3 expression did not, however, always correlate, and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. This suggests that the modes of action of oxaboroles that target trypanosome mRNA processing may extend beyond CPSF3 inhibition.

show abstract

“…Another trypanocidal benzoxaborole (of the amino-methyl subclass) was shown to be subject to a two-step metabolic processing, involving a primary conversion using amine oxidase in host serum to an aldehyde that is further metabolized to a carboxylate via parasite aldehyde dehydrogenase [98]. Another valinate-amide derivative series shows considerable promise for animal African trypanosomiasis too [99].…”

Section: Acoziborole: Mode Of Action and Resistance Riskmentioning

confidence: 99%

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

et al. 2020

View full text Add to dashboard Cite

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

show abstract

Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)

Abstract: Graphical abstract

Cited by 43 publications

References 4 publications

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

Contact Info

Product

Resources

About