Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides.
Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides.
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Toll样受体2-激动剂的结构活性关系导致简化的单酰基脂肪肽。
DOI：
10.1021/jm201071e
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发表时间：
2011-12-08
影响因子：
7.3
通讯作者：
David, Sunil A.
中科院分区：
文献类型：
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作者：
Agnihotri, Geetanjali;Crall, Breanna M.;Lewis, Tyler C.;Day, Timothy P.;Balakrishna, Rajalakshmi;Warshakoon, Hemamali J.;Malladi, Subbalakshmi S.;David, Sunil A.
以S-[2,3-双(棕榈酰氧基)-(2RS)-丙基]-R-半胱氨酰-S-丝氨酸(PAM2CS)化合物为代表的Toll样受体2激动性脂肽是潜在的疫苗佐剂。延续之前报道的该化学型的结构-活性关系，我们确定至少一个最佳长度的酰基 (C16) 和一个适当定向的酯羰基对于 TLR2 激动活性至关重要。棕榈酰酯羰基之一和硫醚之间的间距对于形成重要的氢键至关重要，这一点在脂肽：TLR2 复合物的晶体结构中观察到；因此，同源化合物的活性丧失。青霉胺衍生的类似物也没有活性，可能是由于与 TLR2 中 Ser 12 的羰基存在不利的空间相互作用。该化学型中的硫醚可以用硒醚代替。重要的是，硫代甘油基序可以完全省去，并且可以用硫代乙醇桥代替。这些结果导致了一种结构更简单、合成更容易、水溶性类似物在人类血液中具有强 TLR2 激动活性。
Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.
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影响因子：
6.2
作者：
El Sahly, Hana
通讯作者：
El Sahly, Hana
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
影响因子：
5.5
作者：
Farhat, Katja;Riekenberg, Sabine;Ulmer, Artur J.
通讯作者：
Ulmer, Artur J.
影响因子：
7.3
作者：
Miller, KA;Kumar, EVKS;David, SA
通讯作者：
David, SA
DOI：
10.4161/hv.6.4.10866
发表时间：
2010-04-01
期刊：
HUMAN VACCINES
影响因子：
--
作者：
Hood, Jennifer D.;Warshakoon, Hemamali J.;David, Sunil A.
通讯作者：
David, Sunil A.