Abstract
Introduction: Septic patients have low levels of high-density lipoproteins (HDLs), which is a risk factor. Replenishing HDLs with synthetic HDLs (sHDLs) has shown promise as a therapy for sepsis. This study aimed to develop a computational approach to design and test new types of sHDLs for sepsis treatment. Methods: We used a three-step computational approach to design sHDL nanoparticles based on the structure of HDLs and their binding to endotoxins. We tested the efficacy of these sHDLs in two sepsis mouse models—cecal ligation and puncture (CLP)-induced and P. aeruginosa-induced sepsis models—and assessed their impact on inflammatory signaling in cells. Results: We designed four sHDL nanoparticles: two based on the ApoA-I sequence (YGZL1 and YGZL2) and two based on the ApoE sequence (YGZL3 and YGZL4). We demonstrated that an ApoE-based sHDL nanoparticle, YGZL3, provides effective protection against CLP- and P. aeruginosa-induced sepsis. The sHDLs effectively suppressed inflammatory signaling in HEK-blue or RAW264 cells. Conclusions: Unlike earlier approaches, we developed a new approach that employs computational simulations to design a new type of sHDL based on HDL’s structure and function. We found that YGZL3, an ApoE sequence-based sHDL, provides effective protection against sepsis in two mouse models.
Document Type
Article
Publication Date
3-2025
Digital Object Identifier (DOI)
https://doi.org/10.3390/biom15030397
Funding Information
This study was supported by funding from the National Institute of Health (R35GM141478 and P20GM130456, USA), the US Department of Veterans Affairs (1I01BX004639 and I01BX006408, USA), and the Molecular Modeling and Biopharmaceutical Center (MMBC). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or VA.
Repository Citation
Guo, Ling; Yuan, Yaxia; Zhang, Fang; Zhan, Chang-Guo; and Li, Xiangan, "Computational Design and In Vitro and In Vivo Characterization of an ApoE-Based Synthetic High-Density Lipoprotein for Sepsis Therapy" (2025). Markey Cancer Center Faculty Publications. 422.
https://uknowledge.uky.edu/markey_facpub/422
Notes/Citation Information
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/).