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Title: Structure led drug design for the pentraxins
Author: Jenvey, Michelle Catherine
ISNI:       0000 0001 3590 2918
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2006
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Serum Amyloid P component (SAP) and C-reactive protein (CRP) are members of the 'short' pentraxin sub-family and are composed of five identical subunits arranged symmetrically around a central, hollow pore. CPHPC, the ligand targeted specifically at SAP, consists of two proline residues joined by a six carbon linker and was identified using the Roche compound library. Crystals of SAP in complex with CPHPC were grown in novel crystallisation conditions and diffracted X-rays to a resolution of 1.6 Ǻ. The three-dimensional structure of the complex reveals the formation of an SAP decamer consisting of two molecules of SAP linked by five CPHPC molecules. The peptide bond in the proline residues of the CPHPC molecules can exist in either cis or trans conformation. The identification of the preferred conformation in the CPHPC molecule could potentially increase the potency of the drug in its inhibition of SAP binding to amyloid deposits. The 1.6 Ǻ structure of the SAP-CPHPC suggests that the cis conformation is the preferred state of the proline peptide bond in CPHPC. PCHPC, the ligand targeted at CRP, was created using the rational drug-design approach and is composed of two phosphocholine residues (the natural ligand of CRP) joined by a six carbon linker. The structure of the CRP-PCHPC complex reveals an identical decamer to that formed by the SAP-PCHPC complex with five PCHPC molecules linking two CRP molecules. Alternative approaches to drug design for both SAP and CRP are available that may improve the potency of CPHPC and PCHPC. Multivariate ligands have been designed for both the Shiga-like and cholera toxins and have been shown to improve binding affinities with respect to their monovalent equivalents.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available