# Stichoposide C and Rhizochalin as Potential Aquaglyceroporin Modulators

## TL;DR

This study identifies two natural compounds that can modulate aquaglyceroporins, which are membrane proteins that transport glycerol and water, suggesting potential for new therapeutic applications.

## Contribution

The study discovers stichoposide C and rhizochalin as novel modulators of aquaglyceroporins with potential for drug development.

## Key findings

- Stichoposide C increased glycerol permeability in mouse erythrocyte membranes.
- Rhizochalin decreased glycerol permeability at nanomolar concentrations.
- The peracetyl aglycon of rhizochalin was the most potent inhibitor of glycerol transport among tested derivatives.

## Abstract

Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs are involved in a wide range of physiological functions and pathophysiological conditions, AQP-based therapeutics may have the broad potential for clinical utility, including for disorders of water and energy balance. However, AQP modulators have not yet been developed as suitable candidates for clinical applications. In this study, to identify potential modulators of AQPs, we screened 31 natural products by measuring the water and glycerol permeability of mouse erythrocyte membranes using a stopped-flow light scattering method. None of the tested natural compounds substantially affected the osmotic water permeability. However, several compounds considerably affected the glycerol permeability. Stichoposide C increased the glycerol permeability of mouse erythrocyte membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed that AQP7 was the main aquaglyceroporin in mouse erythrocyte membranes. We further verified the effects of stichoposide C and rhizochalin on aquaglyceroporins using human AQP3-expressing keratinocyte cells. Stichoposide C, but not stichoposide D, increased AQP3-mediated transepithelial glycerol transport, whereas the peracetyl aglycon of rhizochalin was the most potent inhibitor of glycerol transport among the tested rhizochalin derivatives. Collectively, stichoposide C and the peracetyl aglycon of rhizochalin might function as modulators of AQP3 and AQP7, and suggests the possibility of these natural products as potential drug candidates for aquaglyceroporin modulators.