Natural Products: A Promising Avenue for Aquaporin-targeted Drug Discovery

Introduction: Aquaporins are one of the important but challenging targets in drug discovery. They are of great interest owing to their diverse physiological roles in health and diseases and their broad tissue distribution. However, there has been little progress so far in this quest and some have started to doubt whether AQPs are druggable at all. Methods: The Web of Science Core Collection database was used to extract all the literature with different combinations of keywords: “aquaporin”, “compound”, and “natural” from 2013 until 2024. The quality of each publication was further assessed. Results: The identified natural compounds can be divided into three categories: 1) compounds that regulate AQP expression, 2) AQP inhibitors, and 3) inhibitors of AQP-protein interactions. Overall, most reported natural product-based AQP modulators are of terpenoid, polyphenolic and polysaccharide origin. Discussion: Essential challenges in AQP drug development seem to be difficult in modeling selective inhibitors and a lack of robust and reliable in vitro and in vivo assays. Numerous studies report natural products modulating AQPs at the expression level, directly inhibiting AQPs and disturbing their interaction with other intracellular proteins. Since direct targeting of AQPs has not yielded promising results, using natural products as AQP modulators could be a new possibility.