Development of LPS antagonistic therapeutics: synthesis and evaluation of glucopyranoside-spacer-amino acid motifs

Kaeothip, Sophon; Paranjape, Geeta; Terrill, Shana E.; Bongat, Aileen F. G.; Udan, Maria L. D.; Kamkhachorn, Teerada; Johnson, Hope L.; Nichols, Michael R.; Demchenko, Alexei V.

doi:10.1039/c1ra00145k

Cited by 9 publications

(17 citation statements)

References 19 publications

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“…As mentioned above, some therapies have already been developed based on lipid A and utilized in clinic. Therefore, another anticipated important direction in this research area would be to develop new lipid A based therapeutics . However, although in general a series of efficient synthetic strategies have been established for lipid As, their chemical synthesis is still challenging because of their complex structure.…”

Section: Resultsmentioning

confidence: 99%

Progress in the synthesis and biological evaluation of lipid A and its derivatives

Gao

Guo

2017

Medicinal Research Reviews

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Lipid A is one of the core structures of bacterial lipopolysaccharides (LPSs), and it is mainly responsible for the strong immunostimulatory activities of LPS through interactions with the Toll-like receptors and other molecules in the human immune system. To obtain structurally homogeneous and well-defined lipid As and its derivatives in quantities meaningful for various biological studies and applications, their chemical synthesis has become a focal point. This review has provided a survey of significant progresses made in the synthesis of lipid A, and its derivatives that carry diverse saturated and unsaturated lipids, have the phosphate group at its reducing end replaced with a more stable phosphate or carboxyl group, or lack the reducing end phosphate or both phosphate groups, as well as progresses in the synthesis of LPS analogs and other lipid A conjugates. These synthetic molecules have facilitated the elucidation of the structure-activity relationships of lipid A useful for the design and development of lipid A based therapeutics, such as those utilized to treat sepsis, and other medical applications, for example the use of monophosphoryl lipid A as a carrier molecule for the study of fully synthetic self-adjuvanting conjugate vaccines. These topics are also briefly covered in the current review.

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Section: Resultsmentioning

confidence: 99%

Progress in the synthesis and biological evaluation of lipid A and its derivatives

Gao

Guo

2017

Medicinal Research Reviews

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“…Following Peri’s 171 and Fukase’s lead, 134a Demchenko and coworkers 172 proceeded to synthesize Lipid A analogues containing a glucopyranoside core, hydrophobic ether substituents, and an amino acid moiety to provide ionic character to the constructs. The inhibitory activity of compounds 56 and 57 (Fig.…”

Section: Modulation Of the Lps Receptor Complex By Lipid A Analoguesmentioning

confidence: 99%

Modulating LPS Signal Transduction at the LPS Receptor Complex with Synthetic Lipid A Analogues

White

Demchenko

2014

Advances in Carbohydrate Chemistry and Biochemistry

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Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization.

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“…LPS is comprised of three structural regions: lipid A, core oligosaccharide, and O-antigen. Amongst these three regions, the lipid A region is the active part and under normal conditions consists of a polyacylated β(1-6) linked glucosamine disaccharide dependent phospholipid acting as a hydrophobic anchor for LPS, and is responsible for the toxic behavior [3,10]. The KDO (3-deoxy-d-manno-oct-2-ulosonic acid) patch exists in the structure.…”

Section: Introductionmentioning

confidence: 99%

Nanomaterials for Biosensing Lipopolysaccharide

2019

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Lipopolysaccharides (LPS) are endotoxins, hazardous and toxic inflammatory stimulators released from the outer membrane of Gram-negative bacteria, and are the major cause of septic shock giving rise to millions of fatal illnesses worldwide. There is an urgent need to identify and detect these molecules selectively and rapidly. Pathogen detection has been done by traditional as well as biosensor-based methods. Nanomaterial based biosensors can assist in achieving these goals and have tremendous potential. The biosensing techniques developed are low-cost, easy to operate, and give a fast response. Due to extremely small size, large surface area, and scope for surface modification, nanomaterials have been used to target various biomolecules, including LPS. The sensing mechanism can be quite complex and involves the transformation of chemical interactions into amplified physical signals. Many different sorts of nanomaterials such as metal nanomaterials, magnetic nanomaterials, quantum dots, and others have been used for biosensing of LPS and have shown attractive results. This review considers the recent developments in the application of nanomaterials in sensing of LPS with emphasis given mainly to electrochemical and optical sensing.

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Development of LPS antagonistic therapeutics: synthesis and evaluation of glucopyranoside-spacer-amino acid motifs

Cited by 9 publications

References 19 publications

Progress in the synthesis and biological evaluation of lipid A and its derivatives

Progress in the synthesis and biological evaluation of lipid A and its derivatives

Modulating LPS Signal Transduction at the LPS Receptor Complex with Synthetic Lipid A Analogues

Nanomaterials for Biosensing Lipopolysaccharide

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