Selective inhibition of PfA-M1, over PfA-M17, by an amino-benzosuberone derivative blocks malaria parasites development in vitro and in vivo

Abstract

Background Plasmodium falciparum M1 family aminopeptidase is currently considered as a promising target for anti-malarial chemotherapy. Several series of inhibitors developed by various research groups display IC50/Ki values down to nM range on native PfA-M1 or recombinant forms and block the parasite development in culture at µM to sub-µM concentrations. A handful of these inhibitors has been tested on murine models of malaria and has shown anti plasmodial in vivo activity. However, most of these inhibitors do also target the other neutral malarial aminopeptidase, PfA-M17, often with lower Ki values, which questions the relative involvement and importance of each enzyme in the parasite biology.ResultsAn amino-benzosuberone derivative from a previously published collection of chemicals targeting specifically the M1-aminopeptidases has been identified; it is highly potent on PfA-M1 (Ki = 50 nM) and devoid of inhibitory activity on PfA-M17 (no inhibition up to 100 µM). This amino-benzosuberone derivative (T5) inhibits, in the µM range, the in vitro growth of two P. falciparum strains, 3D7 and FcB1, respectively chloroquino-sensitive and resistant. Evaluated in vivo, on the murine non-lethal model of malaria Plasmodium chabaudi chabaudi, this amino-benzosuberone derivative was able to reduce the parasite burden by 44 and 40% in a typical 4-day Peters assay at a daily dose of 12 and 24 mg/kg by intraperitoneal route of administration.ConclusionsThe evaluation of a highly selective inhibitor of PfA-M1, over PfA-M17, active on Plasmodium parasites in vitro and in vivo, highlights the relevance of PfA-M1 in the biological development of the parasite as well as in the list of promising anti-malarial targets to be considered in combination with current or future anti-malarial drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-2032-4) contains supplementary material, which is available to authorized users.

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

“…Thus, we performed medium-throughput screening on a collection of preselected novel analogs of phenylalanine towards pAPN and hAPN. This set of compounds was supplemented with 1-amino-3,3,3-trifluoropropylphosphonic acid (8). The latter one was obtained by standard amidoalkylation of 3,3,3-trifluoropropanal with acetamide and phosphorus trichloride [29,30].…”

“…Inhibition of a certain aminopeptidase activity usually results in profound effects on cell survival and proliferation. This suggests that aminopeptidases should be considered attractive targets for combating devastating human diseases; for instance, cancer, malaria or bacterial infections [5][6][7][8].…”

“…2.2.26. (1-Amino-3,3,3-trifluoropropyl)phosphonic acid(8)(1-Amino-3,3,3-trifluoropropyl)phosphonic acid(8) was synthesized by using the procedure of amidoalkylation of phosphorous trichloride (Oleksyszyn reaction) modified by Ziora and Kafarski, based on Soroka procedure[29,30]. The final product was precipitated from its solution of hydrochloride in ethanol by addition of the pyridine to pH around 6.…”

IgG antibody response against Plasmodium falciparum aminopeptidase 1 antigen in Gabonese children living in Makokou and Franceville

“…Biochemical and enzymatic studies using the purified native enzyme have revealed that this protein of approximately 126 kDa exists in three major maturation forms of approximately 120, 96 and 68 kDa named p120, p96 and p68 . The p35 C‐terminal domain remains associated with p68 to form the p68/p35 enzyme complex, and a recombinant form of the enzyme corresponding to monomeric p96 has been produced and studied . In addition to its key role in hemoglobin degradation, PfA‐M1 could have a possible additional role in late stages of parasite development.…”

“…In addition to its key role in hemoglobin degradation, PfA‐M1 could have a possible additional role in late stages of parasite development. Indeed, the treatments by a T5 inhibitor specific for PfA‐M1‐induced morphological alterations, notably in both trophozoite and schizont stage parasites of the P. falciparum FcB1 strain . Thus, the gathering of evidence on the biological functions of PfA‐M1, particularly its involvement in the breakdown of hemoglobin but also its potential role in the late stages of parasite development, suggests that this protein could be a potential vaccine candidate in malaria vaccine development.…”