In Silico-Aided Design of a Glycan Ligand of Sialoadhesin for in Vivo Targeting of Macrophages

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• 作者：Corwin M. Nycholat ; Christoph Rademacher ; Norihito Kawasaki ; James C. Paulson
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：September 26, 2012
• 年：2012
• 卷：134
• 期：38
• 页码：15696-15699
• 全文大小：326K
• 年卷期：v.134,no.38(September 26, 2012)
• ISSN：1520-5126

文摘

Cell-specific delivery of therapeutic agents using ligand targeting is gaining interest because of its potential for increased efficacy and reduced side effects. The challenge is to develop a suitable ligand for a cell-surface receptor that is selectively expressed on the desired cell. Sialoadhesin (Sn, Siglec-1, CD169), a sialic acid-binding immunoglobulin-like lectin (Siglec) expressed on subsets of resident and inflammatory macrophages, is an attractive target for the development of a ligand-targeted delivery system. Here we report the development of a high-affinity and selective ligand for Sn that is an analogue of the natural ligand and is capable of targeting liposomal nanoparticles to Sn-expressing cells in vivo. An efficient in silico screen of a library of 8400 carboxylic acids was the key to identifying novel 9-N-acyl-substituted N-acetylneuramic acid (Neu5Ac) substituents as potential lead compounds. A small panel of targets were selected from the screen and synthesized to evaluate their affinities and selectivities. The most potent of these Sn ligands, 9-N-(4H-thieno[3,2-c]chromene-2-carbamoyl)-Neu5Ac伪2鈥?Gal尾1鈥?GlcNAc (^TCCNeu5Ac), was conjugated to lipids for display on a liposomal nanoparticle for evaluation of targeted delivery to cells. The ^TCCNeu5Ac liposomes were found to target liposomes selectively to cells expressing either murine or human Sn in vitro, and when administered to mice, they exhibited in vivo targeting to Sn-positive macrophages.