# Ciprofloxacin Inhibits Angiotensin I‑Converting Enzyme (ACE) Activity by Binding at the Exosite, Distal to the Catalytic Pocket

## TL;DR

This study shows that the antibiotic ciprofloxacin inhibits ACE activity by binding at a site away from the enzyme's active region, offering a new approach for developing better ACE inhibitors.

## Contribution

The paper reveals a novel allosteric binding site for ciprofloxacin on ACE, distinct from the catalytic pocket.

## Key findings

- Ciprofloxacin inhibits cACE with an IC50 of 202.7 μM and Ki of 33.8 μM.
- The crystal structure shows ciprofloxacin binds at an exosite overlapping a potential allosteric site.
- This finding provides a scaffold for designing more selective ACE inhibitors.

## Abstract

Human somatic angiotensin
I-converting enzyme is a key zinc metallopeptidase
in cardiovascular regulation that hydrolyzes angiotensin peptides
(Ang I, Ang II), as well as other vasoactive peptides, including kinins
(e.g., bradykinin), substance P, the acetylated tetrapeptide Ac-Ser-Asp-Lys-Pro,
and the amyloid ß-peptide. Because of its enzymatic promiscuity,
ACE and its substrates and products affect many physiological processes,
including blood pressure control, hemopoiesis, reproduction, renal
development/function, fibrosis, and immune response. ACE inhibitors
are among the most important therapeutic agents available today for
the treatment of hypertension, heart failure, coronary artery disease,
renal insufficiency, and general atherosclerosis. However, they need
much improvement because of the side effects seen in patients with
long-term treatment due to nonselective inhibition of the N- and C-domains
of ACE (referred to as nACE and cACE, respectively). Here, we report
that ACE activity can be inhibited by ciprofloxacin, a potent fluoroquinolone
antibiotic (IC50 202.7/K
i 33.8
μM for cACE). In addition, the high-resolution crystal structure
of cACE in complex with ciprofloxacin reveals that it binds at an
exosite away from the active site pocket, overlapping the position
of a potential allosteric site with a different binding mode. The
detailed structural information reported here will provide a useful
scaffold for the design of future potent allosteric inhibitors.