Structure-based development of new cyclic compounds targeting PSD-95 PDZ3 domain

Mandar T Naik; Nandita Naik; Tony Hu; Szu-Huan Wang; John Marshall

doi:10.1101/2023.08.10.552828

Structure-based development of new cyclic compounds targeting PSD-95 PDZ3 domain

bioRxiv [Preprint]. 2023 Aug 11:2023.08.10.552828. doi: 10.1101/2023.08.10.552828.

Authors

Mandar T Naik^{1

2}, Nandita Naik^{1

2}, Tony Hu², Szu-Huan Wang^{1

2}, John Marshall^{1

2}

Affiliations

¹ Department of Molecular Biology, Cell Biology and Biochemistry.
² Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, 02912, United States of America.

Abstract

Aberrant BDNF signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have previously shown that targeting the TrkB / PSD-95 nexus by peptidomimetic inhibitors is a promising approach for therapeutic intervention. Here we used structure-based knowledge to develop a new peptidomimetic compound series that fuses SynGAP-derived peptides to our prototype compound CN2097. These compounds target the PSD-95 PDZ3 domain and adjoining αC helix to achieve bivalent binding that results in up to 7-fold stronger affinity compared to CN2097. These compounds were designed to improve CN2097 specificity for the PDZ3 domain and limited SAR studies have been performed to improve their resistance to proteolysis.

Keywords: Angelman syndrome; Depression; NMR; PSD-95; Structure-based drug design.

Publication types

Preprint

Abstract

Publication types

Grants and funding