Aim: FK506-binding protein 35 from Plasmodium knowlesi (Pk-FKBP35), a member of peptidyl-prolyl cis-trans isomerase (PPIase), is considered a viable target for the development of the novel antimalarial drug targeting zoonotic malaria in Malaysia. While FK506 effectively inhibits this protein, this drug is not applicable due to its immunosuppressive effects. This study aims to assess the inhibitory potential of different collagen hydrolysates (CH) against Pk-FKBP35, as FK506 replacers. Methodology and results: Recombinant full-length Pk-FKBP35 was initially over-expressed using Escherichia coli (BL21) host cells and subsequently purified via affinity chromatography coupled with size-exclusion chromatography. In this study, four distinct CH were employed, originating from bovine, bone broth, fish and swine. The results revealed that all CH inhibited PPIase catalytic activity of Pk-FKBP35 with IC50 values 1.63 mg/mL (bovine CH), 2.97 mg/mL (fish CH), 33.01 mg/mL (swine CH) and 13.91 mg/mL (bone broth CH), which were much higher than that of FK506. Furthermore, these CHs retained the ability of Pk-FKBP35 to inhibit calcineurin phosphatase activity, yet not as extreme as FK506. Conclusion, significance and impact of study The inhibition is predicted due to the presence of proline-rich peptides in CH, which were able to block the substrate binding cavity of Pk-FKBP35. This study suggested that CH might have no serious immunosuppressant effect and is promising for further harnessing for antimalarial compounds

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