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Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.

Niu G, Wang B, Zhang G, King JB, Cichewicz RH, Li J - Sci Rep (2015)

Bottom Line: The inhibition specificity was confirmed by immunofluorescence assays.Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes.Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.

ABSTRACT
Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

No MeSH data available.


Related in: MedlinePlus

The candidate compound identified as P-orlandin.(a) Positive ion mode mass spectrum. (b) Negative ion mode mass spectrum. (c) 13C NMR spectrum. (d) 1H NMR spectrum. (e) Circular dichroism spectrum. (f) Chemical structure of P-orlandin.
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f8: The candidate compound identified as P-orlandin.(a) Positive ion mode mass spectrum. (b) Negative ion mode mass spectrum. (c) 13C NMR spectrum. (d) 1H NMR spectrum. (e) Circular dichroism spectrum. (f) Chemical structure of P-orlandin.

Mentions: Both positive and negative mode electrospray ionization mass spectrometry (ESIMS) were used to analyze the isolate. Based on ions observed at m/z 411.15 [M + H]+ and 821.30 [2M + H]+ (Fig. 8a), as well as 409.15 [M-H]− and 819.30 [2M-H]− (Fig. 8b), we rationalized that the compound possessed a molecular weight of 410 Da. Follow up analysis by high resolution ESIMS enabled us to unambiguously assign the compound a the molecular formula C22H18O8.


Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.

Niu G, Wang B, Zhang G, King JB, Cichewicz RH, Li J - Sci Rep (2015)

The candidate compound identified as P-orlandin.(a) Positive ion mode mass spectrum. (b) Negative ion mode mass spectrum. (c) 13C NMR spectrum. (d) 1H NMR spectrum. (e) Circular dichroism spectrum. (f) Chemical structure of P-orlandin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4593950&req=5

f8: The candidate compound identified as P-orlandin.(a) Positive ion mode mass spectrum. (b) Negative ion mode mass spectrum. (c) 13C NMR spectrum. (d) 1H NMR spectrum. (e) Circular dichroism spectrum. (f) Chemical structure of P-orlandin.
Mentions: Both positive and negative mode electrospray ionization mass spectrometry (ESIMS) were used to analyze the isolate. Based on ions observed at m/z 411.15 [M + H]+ and 821.30 [2M + H]+ (Fig. 8a), as well as 409.15 [M-H]− and 819.30 [2M-H]− (Fig. 8b), we rationalized that the compound possessed a molecular weight of 410 Da. Follow up analysis by high resolution ESIMS enabled us to unambiguously assign the compound a the molecular formula C22H18O8.

Bottom Line: The inhibition specificity was confirmed by immunofluorescence assays.Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes.Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.

ABSTRACT
Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

No MeSH data available.


Related in: MedlinePlus