MB‑32 is a specific, allosteric inhibitor of angiotensin‑converting enzyme 2 (ACE2) with KD of 7.078 and 3.997 uM in SPR and BLI assays, selectively disrupts binding of SARS‑CoV‑2 spike receptor‑binding domain to ACE2, MB-32 is a potent and specific broad-spectrum entry inhibitor of pan-sarbecoviruses.
MB‑32 potently inhibits entry of SARS‑CoV‑2 variants, SARS‑CoV‑1 and diverse bat/pangolin sarbecoviruses in ACE2‑expressing cells, while sparing vesicular stomatitis virus and authentic MERS‑CoV, indicating non‑virucidal, ACE2‑focused activity.
MB‑32 engages a non‑catalytic surface pocket on the ACE2 N‑terminal helix to allosterically disrupt spike attachment.
MB-32 exhibited broad-spectrum activity against SARS-CoV-2 VOCs, with a mean IC50 of 196 nM (range 13.4-532 nM).
MB-32 does not inhibit ACE2 enzymatic activity, does notinhibit TMPRSS2 or Cathepsin L.
MB-32 (60 µg/mouse, 2.33 mg/kg body weight, intranasal (i.n.) administration) demonstrates potent antiviral efficacy in K18-hACE2 transgenic mice and prevents natural transmission against SARS-CoV-2 VOCs.
MB-32 rescues hACE2 transgenic Mice from lethal SARS-CoV-2 infection, with no observable adverse effects.