Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture

Abstract

Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A–D (1–4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics.

Cytosporones W and X: Two Mutually Converting Epimers from a Mangrove Endophytic Fungus Diaporthe sp. ZJHJYZ-1

“…The absolute configuration of C-1 of 1 and 2 were deduced by comparison of the experimental and calculated ECD curves. To reduce the molecular flexibility, the aliphatic side chains were simplified as ethyl groups in the calculation . Moreover, C-1 of 1 and 2 were, respectively, assigned to be S and R .…”

Activity‐Based Protein Profiling Identifies Protein Disulfide‐Isomerases as Target Proteins of the Volatile Salinilactones

“…The protein disulfide‐isomerases, and mainly the PDIA1 isoform, have been intensely studied as anticancer targets, [ 24 ] but they were also found relevant in other indications and processes such as thrombosis, neurodevelopment, viral entry, or ferroptosis. [ 33 , 34 , 35 , 36 ] A series of PDI inhibitors targeting the catalytically active as well as allosteric [ 37 , 38 ] residues have been reported, among them the in vivo active prototype inhibitor PACMA 31. [ 39 ] Compared to optimized PDI inhibitors, natural salinilactones are less potent.…”

Therapeutic effects and molecular mechanisms of natural products in thrombosis

“…Ohwi, can be metabolized by intestinal microorganisms to daidzein after oral administration, and daidzein has more potent antiplatelet aggregation activity than daidzin and puerarin (Choo et al, 2002). Zheng et al (2023) isolated two pairs of antithrombotic natural dihydrochalcones with a novel chemical backbone from Pieris japonica , among them, piericones A was a nanomolar noncompetitive PDI inhibitor, and the inhibitory activity was stronger than the positive drug isoquercetin. It significantly inhibited platelet aggregation and fibrin formation by targeting extracellular PDI.…”