d-Mannose binding, aggregation property, and antifungal activity of amide derivatives of pradimicin A

Wataru Miyanishi; Makoto Ojika; Dai Akase; Misako Aida; Yasuhiro Igarashi; Yukishige Ito; Yu Nakagawa

doi:10.1016/j.bmc.2021.116590

d-Mannose binding, aggregation property, and antifungal activity of amide derivatives of pradimicin A

Bioorg Med Chem. 2022 Feb 1:55:116590. doi: 10.1016/j.bmc.2021.116590. Epub 2021 Dec 27.

Authors

Wataru Miyanishi¹, Makoto Ojika¹, Dai Akase², Misako Aida³, Yasuhiro Igarashi⁴, Yukishige Ito⁵, Yu Nakagawa⁶

Affiliations

¹ Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
² Graduate School of Advanced Science and Engineering, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
³ Office of Research and Academia-Government-Community Collaboration, Hiroshima University, 1-3-2 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8511, Japan.
⁴ Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
⁵ Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan; RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁶ Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Electronic address: yu@agr.nagoya-u.ac.jp.

PMID: 34973516
DOI: 10.1016/j.bmc.2021.116590

Abstract

Pradimicin A (PRM-A) and its derivatives comprise a unique family of antibiotics that show antifungal, antiviral, and antiparasitic activities through binding to d-mannose (Man)-containing glycans of pathogenic species. Despite their great potential as drug leads with an exceptional antipathogenic action, therapeutic application of PRMs has been severely limited by their tendency to form water-insoluble aggregates. Recently, we found that attachment of 2-aminoethanol to the carboxy group of PRM-A via amide linkage significantly suppressed the aggregation. Here, we prepared additional amide derivatives (2-8) of PRM-A to examine the possibility that the amide formation of PRM-A could suppress its aggregation propensity. Sedimentation assay and isothermal titration calorimetry experiment confirmed that all amide derivatives can bind Man without significant aggregation. Among them, hydroxamic acid derivative (4) showed the most potent Man-binding activity, which was suggested to be derived from the anion formation of the hydroxamic acid moiety by molecular modeling. Derivative 4 also exhibited significant antifungal activity comparable to that of PRM-A. These results collectively indicate that amide formation of PRM-A is the promising strategy to develop less aggregative derivatives, and 4 could serve as a lead compound for exploring the therapeutic application of PRM-A.

Keywords: Antibiotic; Antifungal agent; Carbohydrate recognition; Natural product; Structural modification.