Synthetic chemistry advances promising immunosuppressive compounds

27. 05. 2026 

Current immunosuppressive drugs are highly effective, but often associated with severe side effects, such as kidney damage and susceptibility to opportunistic infections. The development of new immunosuppressants with complementary mechanisms of action is therefore of great importance to ensure continued best-standard treatment for transplant patients and patients living with autoimmune diseases.

In collaboration with the Medical University of Vienna and the CeMM Research Center for Molecular Medicine, a team of researchers from the Institute of Organic Chemistry led by Prof. Nuno Maulide investigated whether the naturally occurring macrocyclic compound FR252921 could serve as a starting point for the development of new immunomodulatory agents.

From natural product to synthetic drug design

Using a modular synthetic approach, in which various derivatives of core building blocks could be efficiently combined, the team prepared and systematically evaluated a series of fully synthetic analogues of FR252921 to uncover which molecular features are crucial for biological activity and which could be altered to modulate the compound’s effects. Through this structure–activity relationship (SAR) analysis, which determined the impact of varying functionality across the entire structure, the researchers identified an optimized compound with strongly enhanced activity in primary human immune cells (natural product: 227 nM for IFN-γ and 296 nM for IL-6; synthetic analogue: 14 nM for both pro-inflammatory cytokines).

Original publication:

I. Saridakis, M. Schupp, H. Zhang, T. Leischner, L.M. Gail, K. Günther, M. Drescher, F. Doubek, D. Kaiser, G. Stary, N. Maulide
Target-agnostic SAR mapping and immunological evaluation of (−)-FR252921 and analogs against primary human immune cells. In Chemical Science (2026)

DOI: 10.1039/D5SC09554A

 Scientific contact