Identification of SARS-CoV-2 Spike Palmitoylation Inhibitors That Results in Release of Attenuated Virus with Reduced Infectivity.
Identification of SARS-CoV-2 Spike Palmitoylation Inhibitors That Results in Release of Attenuated Virus with Reduced Infectivity.
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SARS-COV-2尖峰棕榈酰化抑制剂的鉴定会导致释放病毒，并降低感染性。
DOI：
10.3390/v14030531
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发表时间：
2022-03-04
期刊：
影响因子：
--
通讯作者：
Roy A
中科院分区：
文献类型：
--
作者：
Ramadan AA;Mayilsamy K;McGill AR;Ghosh A;Giulianotti MA;Donow HM;Mohapatra SS;Mohapatra S;Chandran B;Deschenes RJ;Roy A
包膜病毒的刺突蛋白是跨膜糖蛋白，通常在翻译后将棕榈酸酯附着在蛋白质胞质面对尾部的半胱氨酸残基上。尖峰蛋白棕榈酰化在病毒生物发生和感染性中的作用作为新型抗病毒药物的潜在靶点正在被积极研究。在这里，我们报道了SARS-CoV-2 S蛋白C端富含半胱氨酸结构域的前五个半胱氨酸残基的棕榈酰化是感染所必需的，棕榈酰化缺陷的突变体在膜融合中是缺陷的。DHHC9棕榈酰转移酶与内质网和高尔基体中的刺突蛋白相互作用并使之棕榈酰化，DHHC9的敲除导致SARS-CoV-2的融合和感染减少。两种基于双哌嗪骨架的DHHC9抑制剂抑制了SARS-CoV-2 S蛋白的棕榈酰化，从而释放出的子代病毒粒子存在融合和感染缺陷。这确立了这些棕榈酰基转移酶抑制剂作为对抗SARS-CoV-2的潜在新干预策略。
The spike proteins of enveloped viruses are transmembrane glycoproteins that typically undergo post-translational attachment of palmitate on cysteine residues on the cytoplasmic facing tail of the protein. The role of spike protein palmitoylation in virus biogenesis and infectivity is being actively studied as a potential target of novel antivirals. Here, we report that palmitoylation of the first five cysteine residues of the C-terminal cysteine-rich domain of the SARS-CoV-2 S protein are indispensable for infection, and palmitoylation-deficient spike mutants are defective in membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 S protein palmitoylation and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.
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影响因子：
16.6
作者：
Cattin-Ortolá J;Welch LG;Maslen SL;Papa G;James LC;Munro S
通讯作者：
Munro S
DOI：
10.1007/978-1-4939-9532-5_16
发表时间：
2019-01-01
期刊：
PROTEIN LIPIDATION: METHODS AND PROTOCOLS
影响因子：
--
作者：
Blanc, Mathieu;David, Fabrice P. A.;van der Goot, F. Gisou
通讯作者：
van der Goot, F. Gisou
影响因子：
4.8
作者：
Lobo, S;Greentree, WK;Deschenes, RJ
通讯作者：
Deschenes, RJ
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U
影响因子：
3.4
作者：
Chen, Jessica J.;Marsden, Autumn N.;Boehning, Darren
通讯作者：
Boehning, Darren