9fm5

PvSub1 Catalytic Domain in Complex with Peptidomimetic Inhibitor (AL-97)

spinqualitylabelsall models 9fm5, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fm5 is a 4 chain structure with sequence from Plasmodium vivax and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.597Å Ligands: 2KY, BUA, CA, GMA, NAG, SO4, VEF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function E6Y8B9_PLAVI Publication Abstract from PubMed After more than 15 years of decline, the Malaria epidemy has increased again since 2017, reinforcing the need to identify drug candidates active on new targets involved in at least two biological stages of the Plasmodium life cycle. The SUB1 protease, which is essential for parasite egress in both hepatic and blood stages, would meet these criteria. We previously reported the structure-activity relationship analysis of alpha-ketoamide-containing inhibitors encompassing positions P4-P2'. Despite compounds with high inhibitory potencies were identified, their antiparasitic activity remained limited, probably due to insufficient cell permeability. Here, we present our efforts to improve it through the N-terminal introduction of basic or hydrophobic moieties and/or cyclization. Compared to our previous reference compounds 1/2 (Ac-Ile/Cpg-Thr-Ala-AlaCO-Asp-Glu(Oall)-NH2), we identified analogues with improved Pf-/PvSUB1 inhibition (IC50 values in the 10-20 nM range) and parasite growth inhibition (up to 98% at 100 muM). The increase in potency was mainly observed when increasing the overall hydrophobicity of the compounds. Conjugation to the cell penetrating peptide octa-arginine was also favorable. Finally, the crystal structure of PvSUB1 in complex with compound 15 has been determined at 1.6 A resolution. Compared to compound 1, this structure extended to the P5 residue and revealed two additional hydrogen bonds. Towards Improved Peptidic alpha-Ketoamide Inhibitors of the Plasmodial Subtilisin-Like SUB1: Exploration of N-Terminal Extensions and Cyclic Constraints.,Puszko AK, Batista FA, Ejjoummany A, Bouillon A, Maurel M, Adler P, Legru A, Martinez M, Ortega Varga L, Hadjadj M, Alzari PM, Blondel A, Haouz A, Barale JC, Hernandez JF ChemMedChem. 2025 Jan 20:e202400924. doi: 10.1002/cmdc.202400924. PMID:39832214 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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