(-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study.

Michael Groll,Sreekumar Vellalath,Henry Nguyen,Daniel Romo

doi:10.3390/md16070240

Abstract

Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (–)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition.

Highlights

Upon the FDA approval of the boronic acid containing inhibitors Velcade® (2003) and Ninlaro®(2015), proteasome inhibitors are of enormous public interest due to their potential as anticancer therapeutics [1,2,3]
The number of studies on selectively and inhibiting the 20S proteasome core particle (CP) has grown exponentially over the past decade and confirmed that some pathogens modulate this fascinating multi-catalytic machinery by small molecules, which have originated during evolution [5]
SalAfunctions functionsas as an an irreversible is aisreversible binder

Summary

Introduction

Upon the FDA approval of the boronic acid containing inhibitors Velcade® (2003) and Ninlaro®(2015), proteasome inhibitors are of enormous public interest due to their potential as anticancer therapeutics [1,2,3]. The number of studies on selectively and inhibiting the 20S proteasome core particle (CP) has grown exponentially over the past decade and confirmed that some pathogens modulate this fascinating multi-catalytic machinery by small molecules, which have originated during evolution [5]. Besides peptidyl inhibitors [6], a distinct class of proteasome ligands has emerged: small molecule β-lactone-γ-lactam natural products and their derivatives. These minimalist inhibitors have incorporated only the most essential structural features required for potent and selective CP blockage, thereby equipping their producing organisms with competitive advantages, while opening up mechanistic insights and therapeutic opportunities to humankind. While the β-lactone moiety is a moderately reactive head group, omuralide (5) selectively blocks the chymotrypsin-like activity of the proteasome

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