TLR2 Agonistic Small Molecules: Detailed Structure-Activity Relationship, Applications, and Future Prospects
TLR2 Agonistic Small Molecules: Detailed Structure-Activity Relationship, Applications, and Future Prospects
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DOI：
10.1021/acs.jmedchem.0c01627
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发表时间：
2021-01-14
影响因子：
7.3
通讯作者：
Salunke, Deepak B.
中科院分区：
文献类型：
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作者：
Kaur, Arshpreet;Kaushik, Deepender;Salunke, Deepak B.
Toll样受体（Toll like receptor，TLR）是识别微生物中病原体相关分子模式（pathogen-associated molecular patterns，PAMP）的模式识别受体（pattern recognition receptor，PRR）。在各种TLR中，TLR 2具有特殊的地位，这是由于其与TLR 1或TLR 6的异源二聚化，扩大了其针对病原体的配体多样性，从而能够感测最广泛的PAMP库。据报道，各种支架可激活TLR 2，包括天然存在的脂蛋白、合成脂肽和小杂环分子。我们描述了TLR 2激动剂支架中的详细SAR，并且还涵盖了TLR 2激动剂与抗原、碳水化合物、聚合物和荧光团缀合的设计和化学。阐述了TLR 2激动剂的递送方法，如抗原的脂化、与聚合物、膦酸和其他接头的缀合以实现表面吸附、脂质体制剂和包封纳米颗粒。晶体结构分析和计算建模也包括促进TLR 2激活的结构特征。
Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the various TLRs, TLR2 has a special place due to its ability to sense the widest repertoire of PAMPs owing to its heterodimerization with either TLR1 or TLR6, broadening its ligand diversity against pathogens. Various scaffolds are reported to activate TLR2, which include naturally occurring lipoproteins, synthetic lipopeptides, and small heterocyclic molecules. We described a detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR2 agonists to antigens, carbohydrates, polymers, and fluorophores. The approaches involved in delivery of TLR2 agonists such as lipidation of antigen, conjugation to polymers, phosphonic acids, and other linkers to achieve surface adsorption, liposomal formulation, and encapsulating nanoparticles are elaborated. The crystal structure analysis and computational modeling are also included with the structural features that facilitate TLR2 activation.