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Endotoxins: Structure, Function and Recognition pp 255–283Cite as

Development of Small-Molecule Endotoxin Sequestering Agents

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Part of the book series: Subcellular Biochemistry ((SCBI,volume 53))

Abstract

Sepsis, otherwise referred to as “blood poisoning” is a serious clinical problem, the incidence of which continues to rise in the US and worldwide despite advances in antimicrobial chemotherapy. The primary trigger in Gram-negative sepsis is endotoxin, a lipopolysaccharide (LPS) constituent of the outer membrane of all Gram-negative bacteria. The structurally highly conserved glycolipid called lipid A is the active moiety of LPS. Lipid A is composed of a hydrophilic, bis-phosphorylated di-glucosamine backbone, and a hydrophobic polyacyl domain. The bis-anionic, amphiphilic nature of lipid A enables it to interact with a variety of cationic hydrophobic ligands, including polymyxin B, a toxic peptide antibiotic which binds to lipid A and neutralizes endotoxicity. Having determined the structural basis of the interaction of polymyxin B with lipid A, our long-term goal has been to rationally design non-peptidic, nontoxic, small-molecule LPS-sequestrants. Our efforts began with defining the central pharmacophore that determined LPS-recognition and -neutralization properties in small molecules, which led to the discovery of a novel lipopolyamine lead, DS-96. DS-96 is an effective LPS-neutralizer, rivaling polymyxin B in a panel of vitro assays, as well as in protecting animals against endotoxicosis. Structure-activity relationships in our effort to rationally design endotoxin sequestering agents, preclinical assessment of hits and leads, and approaches to overcoming issues with toxicity are described in this chapter.

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Abbreviations

AUC:

area under curve

hERG:

human Ether-à-go-go related Gene

IL-1β:

interleukin-1β

IL-6:

interleukin-6

LBP:

LPS-binding acute-phase plasma protein

LPS:

lipopolysaccharide

Mφ:

macrophages

NOE:

nuclear Overhauser effect

NF-κB:

nuclear factor κB

P38 MAPK:

mitogen-activated kinase p38

PK/PD:

pharmacokinetics/pharmacodynamics

PMB:

polymyxin B

TNF-α:

tumor necrosis factor α

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Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS, 66047, USA

    Sunil A. David & Diptesh Sil

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  1. Sunil A. David
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Correspondence to Sunil A. David .

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  1. Dept. Biochemistry, Jiangnan University, Wuxi, Jiangsu, 214122, China, People's Republic

    Xiaoyuan Wang

  2. European Southern Observatory (ESO), Karl-Schwarzschild-Str. 2, Garching, 85748, Germany

    Peter J. Quinn

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David, S.A., Sil, D. (2010). Development of Small-Molecule Endotoxin Sequestering Agents. In: Wang, X., Quinn, P. (eds) Endotoxins: Structure, Function and Recognition. Subcellular Biochemistry, vol 53. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9078-2_12

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