An in vivo approach to structure activity relationship analysis of peptide ligands.

An in vivo approach to structure activity relationship analysis of peptide ligands. Research Abstract Details 

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An in vivo approach to structure activity relationship analysis of peptide ligands. Abstract Text:

Xiaomin Fan,Ruben Venegas,Robert Fey,Henri van der Heyde,Mark A Bernard,Elias Lazarides,Catherine M Woods,

PURPOSE: The goals in this study were several-fold. First, to optimize the in vivo phage display methodology by incorporating phage pharmacokinetic properties, to isolate peptides that target the brain microvasculature, and then to build focused libraries to obtain structure activity relationship information in vivo to identify the optimal targeting motif. MATERIALS AND METHODS: The blood pharmacokinetics of filamentous and T7 phage were evaluated to choose the optimal platform. A randomized peptide library with a motif CX(10)C was constructed in T7 phage and used for in vivo panning. Focused peptide libraries around each structural element of the brain-specific peptide were constructed to perform kinetic structure activity relationship (kSAR) analysis in vivo. To determine potential function, sepsis was induced in mice by LPS administration and four hours later the effect of GST-peptide on adhesion of rhodamine-labelled lymphocytes or CFDA-labelled platelets to pial microvasculature was observed by intravital microscopy. RESULTS: The blood phamacokinetics of T7 was rapid (half-life of 12 min) which aids the clearance of non-specific phage. In vivo panning in brain enriched for isolates expressing the motif CAGALCY. Kinetic analysis of focused libraries built around each structural element of the peptide provided for rapid pharmacophore mapping. The computer modeling data suggested the peptide showed similarities to peptide mimetics of adhesion molecule ligands. GST-CAGALCY but not GST control protein was able to inhibit the rolling and adhesion of labeled platelets to inflamed pial vasculature. GST-CAGALCY had no effect on lymphocyte adhesion. CONCLUSIONS: Incorporating normal blood phamacokinetics of T7 phage into in vivo phage display improves the ability to recover targeting peptide motifs and allows effective lead optimization by kSAR. This approach led to the isolation of a brain-specific peptide, CAGALCY, which appears to function as an effective antagonist of platelet adhesion to activated pial microvasculature.

An in vivo approach to structure activity relationship analysis of peptide ligands. Publishing Authors By Initials

X Fan,R Venegas,R Fey,H van der Heyde,MA Bernard,E Lazarides,CM Woods,

For similar investigative techniques: technology, pharmaceutical research abstracts see: investigative techniques: technology, pharmaceutical research

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An in vivo approach to structure activity relationship analysis of peptide ligands. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Pharmaceutical research

VOLUME: 24

Page Numbers: 868-79

Journal Abbreviation:

ISSN: 0724-8741

DAY: 22

MONTH: 03

YEAR: 2007

An in vivo approach to structure activity relationship analysis of peptide ligands. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8406521

An in vivo approach to structure activity relationship analysis of peptide ligands. Keywords Mesh Terms:

KEYWORDS: Technology, Pharmaceutical

MESH TERMS: methods

Chemical & Substance for Abstract: An in vivo approach to structure activity relationship analysis of peptide ligands. Information

Substance Name: platelet adhesion inhibitor

Registry Number: 0

Grant and Affiliation Information for An in vivo approach to structure activity relationship analysis of peptide ligands.

AFFILIATION: AvantGen, Inc., 9924 Mesa Rim Rd, San Diego, California 92121, USA.

Country: United States

AGENCY: United States NIAID

GRANT: AI40667-06

ACRONYM: AI

MEDLINETA: Pharm Res

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