Design of Coibamide A Mimetics with Improved Cellular Bioactivity.
Design of Coibamide A Mimetics with Improved Cellular Bioactivity.
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DOI：
10.1021/acsmedchemlett.1c00591
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发表时间：
2022-01-13
影响因子：
4.2
通讯作者：
Oishi S
中科院分区：
文献类型：
--
作者：
Kitamura T;Suzuki R;Inuki S;Ohno H;McPhail KL;Oishi S
Coibamide A是一种从巴拿马海洋蓝藻中分离出来的环状沉积肽，通过抑制Sec61转位子显示出强大的细胞毒活性。我们设计了一种coibamide a模拟物，其中coibamide a中甲基和d-MeAla之间的酯连接被烷基连接物取代，以提供具有MeLys（Me）残基的稳定大环支架。利用简单的固相合成方法，对新设计的大环结构进行了构效关系（SAR）研究，重点研究了n -甲基取代模式和氨基酸构型的改变。总之，具有烷基连接体的简化大环支架显著降低了细胞毒性。在对coibamide A原大环支架中的Tyr（Me）位置进行优化后，基于apratoxin A的特征亚结构，鉴定出了具有β-（4-联苯基）丙氨酸（Bph）基团的coibamide A衍生物。coibamide A和apratoxin A之间相似的SAR表明，在Sec61α的管腔端Tyr（Me）侧链的结合位点可能是共享的。
Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure–activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N-methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.
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影响因子：
5.8
作者：
Kazemi S;Kawaguchi S;Badr CE;Mattos DR;Ruiz-Saenz A;Serrill JD;Moasser MM;Dolan BP;Paavilainen VO;Oishi S;McPhail KL;Ishmael JE
通讯作者：
Ishmael JE
霉菌酮通过选择性地阻断SEC61转运，从而颠覆了免疫力。
DOI：
10.1084/jem.20160662
发表时间：
2016-12-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Baron L;Paatero AO;Morel JD;Impens F;Guenin-Macé L;Saint-Auret S;Blanchard N;Dillmann R;Niang F;Pellegrini S;Taunton J;Paavilainen VO;Demangel C
通讯作者：
Demangel C
影响因子：
4
作者：
Lang S;Pfeffer S;Lee PH;Cavalié A;Helms V;Förster F;Zimmermann R
通讯作者：
Zimmermann R
影响因子：
2.7
作者：
Nabika, Ryota;Suyama, Takashi L.;Hau, Andrew M.;Misu, Ryosuke;Ohno, Hiroaki;Ishmael, Jane E.;McPhail, Kerry L.;Oishi, Shinya;Fujii, Nobutaka
通讯作者：
Fujii, Nobutaka
影响因子：
4
作者：
Junne, Tina;Wong, Joanne;Hoepfner, Dominic
通讯作者：
Hoepfner, Dominic