Specific Clearance of Lipopolysaccharide from Blood Based on Peptide Bottlebrush Polymer for Sepsis Therapy

Abstract

Lipopolysaccharide (LPS) is the primary bacterial toxin that is vital to the pathogenesis and progression of sepsis associated with extremely high morbidity and mortality worldwide. However, specific clearance of LPS from circulating blood is highly challenging because of the structural complexity and its variation between/within bacterial species. Herein, a robust strategy based on phage display screening and hemocompatible peptide bottlebrush polymer design for specific clearance of targeted LPS from circulating blood is proposed. Using LPS extracted from Escherichia coli as an example, a novel peptide (HWKAVNWLKPWT) with high affinity (KD < 1.0 nм), specificity, and neutralization activity (95.9 ± 0.1%) against the targeted LPS is discovered via iterative affinity selection coupled with endotoxin detoxification screening. A hemocompatible bottlebrush polymer bearing the short peptide [poly(PEGMEA‐co‐PEP‐1)] exhibits high LPS selectivity to reduce circulating LPS level from 2.63 ± 0.01 to 0.78 ± 0.05 EU mL−1 in sepsis rabbits via extracorporeal hemoperfusion (LPS clearance ratio > 70%), reversing the LPS‐induced leukocytopenia and multiple organ damages significantly. This work provides a universal paradigm for developing a highly selective hemoadsorbent library fully covering the LPS family, which is promising to create a new era of precision medicine in sepsis therapy.

Innovative Chemical Tools to Address Analytical Challenges of Protein Phosphorylation and Glycosylation

“…To overcome this challenge, it is essential to have an artificial reagent, such as polymyxin B, that can bind LPS with high specificity. Recently, we proposed an LPS affinity ligand screening strategy based on phage display and thus developed a ligand-bearing polymer material for precise in situ capture and clearance of LPS …”

“…(D) Schematic showing LPS capture with PES/poly­(PEGMEA- co -PEP-1 microspheres through extracorporeal hemoperfusion for a septic rabbit. Reproduced with permission from ref . Copyright 2023 Wiley-VCH.…”

“…Recently, we proposed an LPS affinity ligand screening strategy based on phage display and thus developed a ligand-bearing polymer material for precise in situ capture and clearance of LPS. 49 As a directed evolution technique, phage display is a highthroughput strategy for screening ligands from the peptide library via top-down affinity panning to any given target. 50 Four iterations of screening against a LPS molecule extracted from Escherichia coli yielded a peptide (HWKAVNWLKPWT, PEP-1 for short) with a substantially higher affinity (K D < 1.0 nM) to the E. coli LPS (Figure 6B).…”

All-Atom Molecular Dynamics Simulations of Uncharged Linear Polymer Bottlebrushes: Effect of the Brush Sizes and the Number of Side-Chain Monomers

“…Polymer chains of bottlebrush architecture or bottlebrush polymers (BBPs), also sometimes denoted as comb-type polymer chains, have been widely investigated over the last several decades and have found extensive applications in areas such as lithium-ion batteries, proton-conducting polymers, solar thermal systems, artificial muscles, vectors, drug carriers, , precision medicines, self-healing networks, − flexible sensors, and electronics. , Such BBPs are typically copolymer systems where one type of polymer forms the backbone, while another type forms the side chains that are grafted on the backbone polymer. A vast variety of BBP systems have been designed by varying (a) the nature of the backbone and side chain polymers; (b) the size or number of monomers of the backbone and side chains; (c) the grafting density of the side chains, etc.…”

Recovering What Matters: High Protein Recovery after Endotoxin Removal from LPS-Contaminated Formulations Using Novel Anti-Lipid A Antibody Microparticle Conjugates

“…Similar results were shown by Shi et al using artificial peptides and a hemocompatible polymer. Furthermore, they demonstrated LPS clearance in extracorporeal in vivo studies [ 18 ]. Despite these improvements in targeting LPS, we rationalized that, by means of an antibody–antigen interaction targeting the Lipid A in LPS, we could further optimize the specific removal of LPS while achieving a high protein yield.…”