Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice.

Summary

Using structure-guided design and molecular dynamics, the authors engineered an Ang1 variant with improved Tie2 binding and demonstrated attenuation of sepsis in mice. The work supports endothelial stabilization via Ang-Tie2 signaling as a therapeutic strategy.

Key Findings

• Structure-guided identification of key Ang1 RBD residues enabled engineering of a variant with enhanced Tie2 affinity.
• The engineered Ang1 variant attenuated sepsis severity in mouse models.
• Molecular dynamics analyses supported the mechanistic basis for improved Ang1–Tie2 interactions.

Clinical Implications

While preclinical, Tie2-agonistic Ang1 variants could complement vasopressors and anti-inflammatory strategies by stabilizing the endothelium and limiting vascular leak in sepsis.

Limitations

• Preclinical animal data without human validation
• Dosing, pharmacokinetics, and safety are not detailed in the abstract

Future Directions

Advance to dose-finding and safety studies, validate efficacy in diverse sepsis models and comorbidities, and assess pharmacokinetics/immunogenicity before early-phase clinical trials.