Dataset Information

Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins.

ABSTRACT: Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria, the use of mefloquine is not highly recommended because of its adverse effects in humans. Mefloquine inhibits the binding of acyl-CoAs to acyl-CoA-binding proteins of Plasmodium falciparum (PfACBPs) and human (hACBP). In this study, we have used molecular dynamics simulation and other computational approaches to investigate the differences of stabilities of mefloquine-PfACBP749 and mefloquine-hACBP complexes. The stability of mefloquine in the binding cavity of PfACBP749 is less than its stability in the binding pocket of hACBP. Although the essential tyrosine residues (tyrosine-30 and tyrosine-33 of PfACBP749 and tyrosine-29 and tyrosine-32 of hACBP) mediate the initial binding of mefloquine to the proteins by ?-stacking interactions, additional temporally longer interactions between mefloquine and aspartate-22 and methionine-25 of hACBP result in stronger binding of mefloquine to hACBP. The higher fluctuation of mefloquine-binding residues of PfACBP749 contributes to the instability of mefloquine in the binding cavity of the protein. On the contrary, in the mefloquine-bound state, the stability of hACBP protein is less than the stability of PfACBP749. The helix-to-coil transition of the N-terminal hydrophobic region of hACBP has a destabilizing effect upon the protein's structure. This causes the induction of aggregation properties in the hACBP in the mefloquine-bound state. Taken together, we describe the mechanistic features that affect the differential dynamic stabilities of mefloquine-bound PfACBP749 and hACBP proteins.

SUBMITTER: Kumar A

PROVIDER: S-EPMC7841788 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Differential Stabilities of Mefloquine-Bound Human and <i>Plasmodium falciparum</i> Acyl-CoA-Binding Proteins.

Kumar Abhishek A Ghosh Debasish Kumar DK Ranjan Akash A

ACS omega 20210111 3

Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria, the use of mefloquine is not highly recommended because of its adverse effects in humans. Mefloquine inhibits the binding of acyl-CoAs to acyl-CoA-binding proteins of <i>Plasmodium falciparum</i> (PfACBPs) and human (hACBP). In this study, we have used molecular dynamics simulation and other computational approaches to investigate ...[more]

PMID: 33521428

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Project description:BackgroundArtemisinin-based combination therapy (ACT) is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ) have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS) combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam, Mephaquin, and Mefloquina-AC Farma) given in combination with artesunate.MethodsThirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1) Lariam, (2) Mephaquin, or (3) Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours), 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol.Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data.ResultsBy day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14-15 days and time to maximum plasma concentration of 45-52 hours. The maximal concentration (Cmax) and interquartile range was 2,820 ng/ml (2,614-3,108) for Lariam, 2,500 ng/ml (2,363-2,713) for Mephaquin, and 2,750 ng/ml (2,550-3,000) for Mefloquina AC Farma. The pharmacokinetics of the three formulations were generally similar, with the exception of the Cmax of Mephaquin which was significantly different to that of Lariam (p = 0.04).ConclusionAll three formulations had similar pharmacokinetics; in addition, the pharmacokinetics seen in this Peruvian population were similar to reports from other ethnic groups. All patients rapidly cleared their parasitaemia with no evidence of recrudescence by Day 56. Continued surveillance is needed to ensure that patients continue to receive optimal therapy.

Project description:As plant seed oils provide animals with essential fatty acids (FAs), genes that regulate plant lipid metabolism have been used in genetic manipulation to improve dietary seed oil composition and benefit human health. Herein, the Arabidopsis thaliana cytosolic acyl-CoA-binding proteins (AtACBPs), AtACBP4, AtACBP5, and AtACBP6 were shown to play a role in determining seed oil content by analysis of atacbp (atacbp4, atacbp5, atacbp6, atacbp4atacbp5, atacbp4atacbp6, atacbp5atacbp6, and atacbp4atacbp5atacbp6) seed oil content in comparison with the Col-0 wild type (WT). Triacylglycerol (TAG) composition in electrospray ionization-mass spectrometer (ESI-MS) analysis on atacbp6 seed oil showed a reduction (-50%) of C58-TAGs in comparison with the WT. Investigations on fatty acid composition of atacbp mutants indicated that 18:2-FA accumulated in atacbp6 and 18:3-FA in atacbp4, both at the expense of 20:1-FA. As TAG composition can be modified by acyl editing through phosphatidylcholines (PC) and lysophosphatidylcholines (LPC), total PC and LPC content in atacbp6 mature seeds was determined and ESI-MS analysis revealed that LPC had increased (+300%) at the expense of PC. Among all the 14 tested PC species, all (34:1-, 34:2-, 34:3-, 34:4-, 34:5-, 34:6-, 36:2-, 36:3-, 36:5-, 36:6-, 38:2-, 38:3-, and 38:4-PCs) but 36:4-PC were lower in atacbp6 than the WT. In contrast, all LPC species (16:0-, 18:1-, 18:2-, 18:3-, and 20:1-LPC) examined were elevated in atacbp6. LPC abundance also increased in atacbp4atacbp5, but not atacbp4 and atacbp5. Interestingly, when LPC composition in atacbp4atacbp5 was compared with atacbp4 and atacbp5, significant differences were observed between atacbp4atacbp5 and each single mutant, implying that AtACBP4 and AtACBP5 play combinatory roles by affecting LPC (but not PC) biosynthesis. Furthermore, PC-related genes such as those encoding acyl-CoA:lysophphosphatidylcholine acyltransferase (LPCAT1) and phospholipase A2 alpha (PLA2α) were upregulated in atacbp6 developing seeds. A model on the role of AtACBP6 in modulating TAG through regulating LPCAT1 and PLA2α expression is proposed. Taken together, cytosolic AtACBPs appear to affect unsaturated TAG content and are good candidates for engineering oil crops to enhance seed oil composition.

Project description:BackgroundDeclining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment.ObjectiveThis study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant P. falciparum malaria.MethodsData collected during 2008-2009 from 124 patients with uncomplicated P. falciparum malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients' adherence and parasite biomass.ResultsThe developed PK/PD models well described with clinically observed data. For mefloquine-resistant P. falciparum, a three-day standard regimen of artesunate-mefloquine is suitable (>50% efficacy) only when the level of parasite sensitivity was < 1.5-fold of the cut-off level (IC50 < 36 nM). For mefloquine-sensitive parasite with IC50 < 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC50 of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C336h (>408 ng.mL-1) or Cmax/IC50 (>130.1 g.m/M), and Cmax/IC50 (>381.2 g.m/M), respectively.ConclusionsClinical use of a three-day standard artesunate-mefloquine is suitable only when the IC50 of P. falciparum isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC50 is lower than 23.19 nM.

Dataset Information

Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins.

Publications

Differential Stabilities of Mefloquine-Bound Human and <i>Plasmodium falciparum</i> Acyl-CoA-Binding Proteins.

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