Haataja Sauli, Verma Priya, Fu Ou, Papageorgiou Anastassios C, Pöysti Sakari, Pieters Roland J, Nilsson Ulf J, Finne Jukka
Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, POB 124, 221 00, Lund, Sweden.
Chemistry. 2018 Feb 6;24(8):1905-1912. doi: 10.1002/chem.201704493. Epub 2018 Jan 5.
Host cell surface carbohydrate receptors of bacterial adhesins are attractive targets in anti-adhesion therapy. The affinity of carbohydrate ligands with adhesins is usually found in the low μm range, which poses a problem for the design of effective inhibitors useful in therapy. In an attempt to increase the inhibitory power of carbohydrate ligands, we have combined the approach of chemical modification of ligands with their presentation as multivalent dendrimers in the design of an inhibitor of streptococcal adhesin SadP binding to its galactosyl-α1-4-galactose (galabiose) receptor. By using a phenylurea-modified galabiose-containing trisaccharide in a tetravalent dendrimeric scaffold, inhibition of adhesin at a low picomolar level was achieved. This study has resulted in one of the most potent inhibitors observed for bacterial adhesins and demonstrates a promising approach to develop anti-adhesives with the potential of practical applicability.
细菌黏附素的宿主细胞表面碳水化合物受体是抗黏附治疗中颇具吸引力的靶点。碳水化合物配体与黏附素的亲和力通常在低微摩尔范围内，这给设计用于治疗的有效抑制剂带来了问题。为了提高碳水化合物配体的抑制能力，我们在设计链球菌黏附素SadP与其半乳糖基-α1-4-半乳糖（半乳糖二糖）受体结合的抑制剂时，将配体化学修饰方法与其作为多价树枝状大分子的呈现方式相结合。通过在四价树枝状支架中使用苯基脲修饰的含半乳糖二糖的三糖，实现了在低微摩尔水平对黏附素的抑制。这项研究产生了一种观察到的对细菌黏附素最有效的抑制剂之一，并证明了一种开发具有实际应用潜力抗黏附剂的有前景方法。
