Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation

Abstract

Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

“…Although PanK activity was previously measured in lysates from the P. falciparum blood stage parasites Spry et al, 2005;Spry et al, 2018;Tjhin et al, 2018), no previous report has described successful expression of bacterial recombinant PfPanK (Hart et al, 2016). In this study, we have developed the overexpression and purification of active PfPanK using an Escherichia coli expression system, and biochemically characterized PfPanK.…”

Overcoming synthetic challenges in targeting coenzyme A biosynthesis with the antimicrobial natural product CJ-15,801

“…when the 1,3-diol was protected by using an acetonide and the carboxylic acid with an allyl, tert-butyl or TMSE ester (Table 2, entries 1-6). 8,10,17,18 In all cases, deprotection of these intermediates proceeded in a step-wise manner, with the acetonide being removed first from 5a and 5c, while in the case of 5d it was removed only after deprotection of the TMSE ester. This approach gave yields of between 40% and 61% for the deprotection steps.…”

A novel heteromeric pantothenate kinase complex in apicomplexan parasites

“…Our data indicate that T. gondii parasites are unable to scavenge sufficient downstream intermediates in the CoA biosynthesis pathway, including CoA, from their host cells, for their survival, and therefore must maintain their own active CoA biosynthesis pathway. The requirement for CoA biosynthesis in T. gondii, coupled with the intense investigation of this pathway as a drug target in P. falciparum [27,[39][40][41][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67], suggests that further characterisation of TgPanK, and the CoA biosynthesis pathway in T. gondii, could yield novel drug targets for chemotherapy.…”