Characterization of sulfated polysaccharide activity against virulent Plasmodium falciparum PHISTb/RLP1 protein.

Autor:	Mutisya JM; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya.; Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya., Mobegi VA; Department of Biochemistry, University of Nairobi, Nairobi, Kenya., Kinyua JK; Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya., Kivecu MN; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Okoth RO; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Chemwor GC; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Mwakio EW; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Cheruiyot AC; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Yeda RA; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Okello CO; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Juma JA; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Opot BH; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Juma DW; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Roth AL; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Akala HM; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya., Andagalu BM; Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya.
Jazyk:	angličtina
Zdroj:	F1000Research [F1000Res] 2020 Oct 23; Vol. 9, pp. 1268. Date of Electronic Publication: 2020 Oct 23 (Print Publication: 2020).
DOI:	10.12688/f1000research.26756.1
Abstrakt:	Background: The emergence of artemisinin resistance in South East Asia calls for urgent discovery of new drug compounds that have antiplasmodial activity. Unlike the classical compound screening drug discovery methods, the rational approach involving targeted drug discovery is less cumbersome and therefore key for innovation of new antiplasmodial compounds.  Plasmodium falciparum (Pf) utilizes the process of host erythrocyte remodeling using Plasmodium-helical interspersed sub-telomeric domain (PHIST) containing proteins, which are amenable drug targets. The aim of this study is to identify inhibitors of PHIST from sulfated polysaccharides as new antimalarials. Methods: 251 samples from an ongoing study of epidemiology of malaria and drug resistance sensitivity patterns in Kenya were sequenced for PHISTb/RLP1 gene using Sanger sequencing. The sequenced reads were mapped to the reference Pf3D7 protein sequence of PHISTb/RLP1 using CLC Main Workbench. Homology modeling of both reference and mutant protein structures was achieved using the LOMETs tool. The models were refined using ModRefiner for energy minimization. Ramachandran plot was generated by ProCheck to assess the conformation of amino acids in the protein model. Protein binding sites predictions were assessed using FT SITE software. We searched for prospective antimalarials from PubChem. Docking experiments were achieved using AutoDock Vina and analysis results visualized in PyMOL. Results: Sanger sequencing generated 86 complete sequences. Upon mapping of the sequences to the reference, 12 non-synonymous single nucleotide polymorphisms were considered for mutant protein structure analysis. Eleven drug compounds with antiplasmodial activity were identified. Both modelled PHISTb/RLP1 reference and mutant structures had a Ramachandran score of >90% of the amino acids in the favored region. Ten of the drug compounds interacted with amino acid residues in PHISTb and RESA domains, showing potential activity against these proteins. Conclusion: These interactions provide lead compounds for new anti-malarial molecules. Further in vivo testing is recommended. Competing Interests: No competing interests were disclosed. (Copyright: © 2020 Mutisya JM et al.)
Databáze:	MEDLINE
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