# Anti-Inflammatory Lindolin Alkaloids Repress the Transcription of the Microsomal Prostaglandin E2 Synthase‑1 Gene in Macrophages

## TL;DR

A new compound from a rare fungus reduces inflammation by blocking a key gene in immune cells, offering a potential new treatment approach.

## Contribution

Lindolin alkaloids are shown to selectively inhibit mPGES-1 gene expression in macrophages, offering a novel anti-inflammatory mechanism.

## Key findings

- Lindolins specifically suppress mPGES-1 gene expression in M1 macrophages, reducing PGE2 production.
- Four lindolin analogs with enhanced anti-inflammatory activity share a structural feature with tranilast.
- Early-diverging fungi are identified as a promising source of pharmaceutical compounds.

## Abstract

The known indole-3-acetyl anthranilate
lindolin A from
the early-diverging
fungus Linderina pennispora, along
with three novel semisynthetic congeners, were identified as selective
inhibitors of prostaglandin E2 (PGE2) formation.
Lindolins specifically suppress the expression of the microsomal prostaglandin
E2 synthase-1 (mPGES-1) gene in M1-polarized human macrophages,
resulting in markedly reduced mPGES-1 protein levels and a consequent
decrease in PGE2 production, while leaving other lipid
mediators largely unaffected. The biosynthesis of lindolins involves
the promiscuous N-acyltransferase LinB, which accepts
a variety of substituted anthranilic acids as acceptor substrates,
thereby enabling the in vitro generation of an analog
library. Structure–activity relationship studies revealed that
four lindolin analogs with enhanced anti-inflammatory activity possess
an ortho-substituted carboxyl group, a structural
feature shared with the clinically used antiallergic drug tranilast.
Due to their high selectivity toward the mPGES-1 gene
expression, lindolins represent promising lead structures for the
development of selective mPGES-1 inhibitors with a novel mode of action.
Moreover, these findings highlight early-diverging fungi as underestimated
source of compounds with pharmaceutical potential.