Chemical inhibition of PIN auxin transporters by the anti-inflammatory drug Naproxen

Abstract

The phytohormone auxin plays central roles in many growth and developmental processes in plants. Development of chemical tools targeting the auxin pathway is useful for both plant biology and agriculture. Here we uncover that Naproxen, a synthetic compound with anti-inflammatory activity in humans, acts as an auxin transport inhibitor targeting PIN transporters in plants. Physiological experiments indicate that exogenous Naproxen treatment affects pleiotropic auxin-regulated developmental processes. Further cellular and biochemical evidence supports that Naproxen suppresses auxin transport, specifically PIN-mediated auxin efflux. Moreover, biochemical and structural analysis confirms that Naproxen binds directly to PIN1 protein, via the same binding cavity as the IAA substrate. Thus, by combining cellular, biochemical, and structural approaches, this study well establishes that Naproxen is a PIN inhibitor and elucidates the underlying mechanisms. Further use of the compound may advance our understanding on the molecular mechanisms of PIN-mediated auxin transport, and expand our toolkit in auxin biology and agriculture.

A unique mutation in PIN‐FORMED1 and a genetic pathway for reduced sensitivity of Arabidopsis roots to N‐1‐naphthylphthalamic acid

“…Since the V583 residue is required for the docking of NPA, but not for IAA, we assumed that the P584L substitution near the V583 residue reduces competition of NPA with IAA (Figure 4C-E). In a recent report, higher concentrations of naproxen, an anti-inflammatory drug, inhibit root growth like NPA (Xia et al, 2023).…”

“…Since the V583 residue is required for the docking of NPA, but not for IAA, we assumed that the P584L substitution near the V583 residue reduces competition of NPA with IAA (Figure 4C‐E). In a recent report, higher concentrations of naproxen, an anti‐inflammatory drug, inhibit root growth like NPA (Xia et al, 2023). Naproxen and NPA may have a similar binding pattern with PIN1: the naphthalene groups of naproxen are stacked between the hydrophobic residues of PIN1, including the I582 and V583 residues (Xia et al, 2023).…”

“…In a recent report, higher concentrations of naproxen, an anti‐inflammatory drug, inhibit root growth like NPA (Xia et al, 2023). Naproxen and NPA may have a similar binding pattern with PIN1: the naphthalene groups of naproxen are stacked between the hydrophobic residues of PIN1, including the I582 and V583 residues (Xia et al, 2023). In future investigations, determining the binding affinity of IAA and NPA inside the PIN1 P584L protein using methods like isothermal titration calorimetry and surface plasma resonance is necessary.…”