Development of a Recombinant Ang1 Variant with Enhanced Tie2 Binding and Its Application to Attenuate Sepsis in Mice

Overview

Journal Sci Adv

Date 2025 Jan 15

PMID 39813336

Authors

Rui Wang

Hao Li

Zhinuo Xie

Meijuan Huang

Peng Xu

Cai Yuan

Jinyu Li

Robert Flaumenhaft

Mingdong Huang

Longguang Jiang

Affiliations

Soon will be listed here.

Abstract

The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that MetArg (M436R) and AlaAsp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBD, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1 enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1 as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.

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