Publication Date

2018

Journal Title

PLoS ONE

Abstract

© 2018 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that mediates inflammatory responses after infection or injury. Previously, we reported a peptide inhibitor of HMGB1 (P5779) that acts by directly interrupting HMGB1/MD-2 binding. Here, fingerprint similarity search and docking studies suggest folic acid derived-drugs function as P5779 mimetopes. Molecular dynamic (MD) simulation studies demonstrate that folic acid mimics the binding of P5779 at the TLR4 and MD-2 intersection. In surface plasmon resonance (SPR) studies, these drugs showed direct binding to TLR4/MD-2 but not HMGB1. Furthermore, these P5779 mimetopes inhibit HMGB1 and MD-2 binding and suppress HMGB1-induced TNF release in human macrophages in the nanomolar range. We assert from our findings that their demonstrated anti-inflammatory effects may be working through TLR4-dependent signaling.

Volume Number

13

Issue Number

2

Document Type

Article

Status

Faculty, Northwell Researcher

Facility

School of Medicine; Northwell Health

Primary Department

Molecular Medicine

Additional Departments

General Internal Medicine

PMID

29447234

DOI

10.1371/journal.pone.0193028


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