We are excited to share our latest work on the identification of a small molecule targeting the SLC15A4-TASL complex in collaboration with Giulio Superti-Furga’ and Leonhard Heinz’ labs.
After discovering the TASL-SLC15A4 complex few years ago, we designed a screening assay to monitor its assembly and identified an inhibitory compound, which we named Feeblin/C5. Feeblin impairs TASL binding to SLC15A4 and blocks TLR7/8-induced inflammatory responses.
Cryo-EM structure SLC15A4-Feeblin, obtained in collaboration with the Maojun Yang lab, shows that Feeblin locks SLC15A4 in an outward open conformation, which is incompatible with TASL binding.
Our study provides the proof-of-principle that the SLC15A4-TASL complex is “druggable” and a promising therapeutic target for SLE and related autoimmune diseases.

Feeblin/C5 is shown as dark yellow sticks bound to its binding pocket in human SLC15A4 in its outward-open conformation.

Thanks and congrats to all co-authors!

You can know more about the study in these two peer-reviewed articles:

“A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity” was published in Nature Communications on 20 October 2023, DOI: 10.1038/s41467-023-42070-3.

“Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling” was published in Nature Communications on 20 October 2023, DOI: 10.1038/s41467-023-42210-9.

You can check also more news featuring the discovery at CeMM News.