Conjugation to Albumin‐Binding Molecule Tags as a Strategy to Improve Both Efficacy and Pharmacokinetic Properties of the Complement Inhibitor Compstatin. Issue 10 (23rd July 2014)

• Record Type: Journal Article
• Authors: Huang, Yijun; Reis, Edimara S.; Knerr, Patrick J.; van der Donk, Wilfred A.; Ricklin, Daniel; Lambris, John D.
• Is Part Of: ChemMedChem. Volume 9:Issue 10(2014:Oct.)
• Page Start: 2223
• Page End: 2226
• Publication Date: 2014-07-23
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402212
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The compstatin family of complement inhibitors has shown promise in various immuno‐inflammatory disorders. Although recent analogues show beneficial pharmacokinetics, further extension of the plasma half‐life is expected to benefit systemic application of these peptidic inhibitors. We therefore synthesized conjugates of compstatin analogues and albumin‐binding molecules (ABM) to increase circulatory residence. Equilibrium dialysis in complement‐depleted serum showed a marked increase in plasma protein binding from &lt;8 % to &gt;99 % for a resulting chimera (ABM2‐Cp20). Further analysis confirmed interaction with albumin from different species, primarily via site II. Importantly, ABM2‐Cp20 bound 20‐fold stronger to its target protein C3b (<italic>K</italic>_D=150 p<sc>M</sc>) than the parent peptide. Kinetic and in silico analysis suggested that ABM2 occupies a secondary site on C3b and improves the dissociation rate via additional contacts. Addition of an ABM modifier thereby not only improved plasma protein binding but also produced the most potent compstatin analogue to date with potential implications for the treatment of systemic complement‐related diseases.</p> </abstract>