n stream signaling pathways. Only peptides containing the either KTISW or HYNE motifs were able to bind to PfPP1c. However, the incubation of these peptides with PfPP1 or their injection into oocytes failed either to inhibit phosphatase activity or to promote GVBD respectively. However, the pre injection of the KTISW and HYNE peptides did block the PfI2 dependent GVBD. Moreover, there was no interaction between enopus PP1 and PfI2 in e tracts of oocytes pre injected with the KTISW or HYNE peptides. This encouraged us to investigate the ability of these peptides to inhibit the growth of P. falciparum. To do this, the capacity of the peptides to cross membranes was first improved by including a short basic peptide, which has been shown to be highly efficient in increasing the permeability of peptides and to promote accumulation within infected red blood cells.
Peptides encompassing the RV F degenerate motif R K 0 1 V I 0 1 F W inhibited the growth of 3D7 P. falciparum strain at low micro molar concentrations. The substitution of amino acids essential for binding with PfPP1 validated that the growth inhibition Inhibitors,Modulators,Libraries was RV F dependent. The difference in the observed IC50 values of KTISW and KVVRW containing peptides could be related to a higher affinity of the latter for PfPP1 and the fact that it proved able to accumulate not only in merozoites but also in parasites within infected Inhibitors,Modulators,Libraries red blood cells. Une Inhibitors,Modulators,Libraries pectedly, the second PP1 binding Inhibitors,Modulators,Libraries peptide containing the HYNE motif, al though it was found functional in oocyte model, was not active as an antiplasmodial suggesting that native PfI2 e pressed by P.
falciparum could displace the HYNE peptide. One possible e planation for the anti parasitic activity of RV F containing peptides is that an increase in PP1 activity due to its reduced interaction with regulators Dacomitinib could result in uncontrolled protein dephosphorylation, leading in turn to an inhibition of parasite differentiation growth. This implies that each competing active peptide can block its respective protein but that cross inhibition of other partners using the same docking site cannot be e cluded. These peptides might prove very useful as fun damental research tools to dissect pathways and processes controlled by PP1 in Plasmodium falciparum. Conclusion In this study we report the molecular analysis and func tional role of the inhibitor 2 regulator, a gene product that binds to and controls the activity of PfPP1.
Structure activity studies of this regulator led to the identification of binding kinase inhibitor Ponatinib functional motifs of PfI2. In addition, peptides corresponding to the RV F motif e hibit anti plasmodial activity against blood stage parasites in vitro. Although, additional investigations are required to better define the interaction of competing peptides in the parasite, the proof of concept finding of derived peptides from regula tors of PfPP1 that inhibit the binding of PfI2 to PfPP1 and, in consequence, parasite growth is an important advance. It opens new avenues f
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