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Human Angiotensin-Converting Enzyme 2-Specific Benzothiazole Allosteric Inhibitor against Pan-Sarbecoviruses

ABSTRACT: Emerging SARS-CoV-2 variants of concern (VOCs) have demonstrated exceptional transmissibility and a strong dependence on the cellular receptor human angiotensin-converting enzyme 2 (hACE2). In this study, we present MB-32, a benzothiazole-based small molecule allosteric inhibitor of hACE2, which exhibits broad-spectrum antiviral activity against multiple SARS-CoV-2 VOCs, SARS-CoV-1, and bat/pangolin-derived sarbecoviruses. MB-32 effectively inhibits lung infections and prevents contact transmission of the SARS-CoV-2 Omicron in animal models. We subsequently studied the binding site of MB-32 on hACE2 using formaldehyde (FA) crosslinking coupled with mass spectrometry. To investigate FA crosslinking modifications, we utilized the mass of 558.22 Da, which is derived from the monoisotopic mass of MB-32 (534.22 Da) combined with a 2-carbon (24 Da) bridge, using PEAKS Studio 11. Focusing on four fixed amino acid type—saspartic acid, tyrosine, arginine, and lysine—we detected a 558.22 Da adduct in the combined mass of two peptides containing Y83 (EQSTLAQMY83PLQEIQNLTVK) and K94 (EQSTLAQMYPLQEIQNLTVK94), with high confidence scores of 1000.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Sarbecovirus

DISEASE(S): Covid-19

SUBMITTER: Kong Hung SZE

LAB HEAD: Dr. Liu Li

PROVIDER: PXD075140 | Pride | 2026-05-01

REPOSITORIES: Pride

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			Action	DRS
	1.p	Other
	2.p	Other
	ACE2_DMSOd6.raw	Raw
	ACE2_MB_32.raw	Raw
	ChanJ_ID_CPOS-230228-BY-16841_Results.xlsx	Xlsx

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