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Developing lipopolysaccharide-neutralizing peptides through modular high throughput screening strategies

Award Number: R03AI139916
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Gram-negative bacterial infections account for more than half a million severe sepsis cases every year in the United States, where a major pathogenic factor is lipopolysaccharides (LPS) and their corresponding toxic component, lipid A. Minimizing serum lipid A level was expected to be an effective therapy for managing severe sepsis. This hypothesis has been validated in clinical studies. For instance, hemoperfusion methods using immobilized polymyxin B (PB) to remove circulating LPS have proven beneficial. However, common LPS- neutralizing agents, such as PB, are highly toxic, therefore have rather restricted therapeutic applications. In addition, the repertoire of LPS-binding agents is limited by their naturally occurring precursors. On the other hand, due to the difficulties in targeting the lipid A moiety, de novo discovery of LPS-neutralizing compounds remains challenging. Herein, a modular screening approach will be implemented to identify lipid A-specific binders form cyclic peptide libraries. A rhodamine-phenylboronic acid conjugate will be used to stain the polysaccharide part in LPS, which allows differentiating polysaccharide-specific binders from lipid A-specific ones. Three orthogonal methods will be employed to validate the affinity and specificity of identified peptides. Further in vitro validations will be performed on bone marrow-derived macrophages and human peripheral blood mononuclear cells to test the bioactivity. These cells will be challenged with LPS in conjunction with the peptides and their cytokine production will be evaluated. Lower cytokine levels indicate better LPS neutralization effects. Ultimately, the goal is to identify pan-LPS reactive peptides that exhibit high LPS-neutralization capability as well as low cytotoxicity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = -$445 )
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	000	2	11/5/2021	NON-COMPETING CONTINUATION	-$445
														Subtotal = -$445

Issue Date FY: 2020 ( Subtotal = $68,034 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	000	2	3/31/2020	NON-COMPETING CONTINUATION	$68,034
														Subtotal = $68,034

Issue Date FY: 2019 ( Subtotal = $68,413 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	000	1	5/9/2019	NEW	$68,413
														Subtotal = $68,413

Grand Total All Awards = $136,002

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Developing lipopolysaccharide-neutralizing peptides through modular high throughput screening strategies

Award Number: R03AI139916

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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