Selective Inhibition of the Interaction between SARS-CoV-2 Spike S1 and ACE2 by SPIDAR Peptide Induces Anti-Inflammatory Therapeutic Responses.
Selective Inhibition of the Interaction between SARS-CoV-2 Spike S1 and ACE2 by SPIDAR Peptide Induces Anti-Inflammatory Therapeutic Responses.
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DOI：
10.4049/jimmunol.2100144
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发表时间：
2021-11-15
期刊：
影响因子：
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通讯作者：
Pahan K
中科院分区：
文献类型：
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作者：
Paidi RK;Jana M;Mishra RK;Dutta D;Pahan K
重症监护病房的许多新冠肺炎患者都遭遇了细胞因子风暴。虽然可以使用抗炎疗法来治疗这个问题，但这些治疗往往会导致免疫抑制。由于宿主细胞上的血管紧张素转换酶2(ACE2)是严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)的受体，为了揭示SARS-CoV-2特异性的抗炎分子，我们设计了一个与ACE2受体S_1相互作用结构域(Spike S1-Interaction Domines of ACE2 Receptor，SpiDAR)相对应的六肽，它能抑制假型SARS-CoV-2诱导的人A549肺细胞中致炎分子的表达，但不能抑制水泡性口炎病毒(VSV)的表达。相应地，野生型(Wt)而非突变型(M)SpiDAR抑制SARS-CoV-2尖峰S1诱导的人肺细胞中NF-κB的激活以及IL-6和IL-1β的表达。然而，wtSPIDAR仍不能减少肿瘤坏死因子κ、HIV-1Tat和病毒双链α模拟聚IC诱导的肺细胞中NF-RNAB的激活和促炎分子的表达，表明其作用的特异性。WtSPIDAR，而不是mSPIDAR，也阻止了SARS-CoV-2的ACE2和尖峰S1之间的联系，并抑制了假型SARS-CoV-2进入表达ACE2的人HEK293细胞，但不抑制VSV。此外，鼻腔治疗wtSPIDAR，而不是mSPIDAR，可抑制肺组织中NF-κB的激活，保护肺，降低发热，改善心功能，并增强SERS-CoV-2尖峰S1中毒小鼠的运动活动。因此，通过wtSPIDAR选择性靶向SARS-CoV-2尖峰S1与ACE2的相互作用可能对新冠肺炎有利。
Many COVID-19 patients in intensive care units suffer from cytokine storm. Although anti-inflammatory therapies are available to treat the problem, very often these treatments cause immunosuppression. Since angiotensin-converting enzyme 2 (ACE2) on host cells serves as the receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), in order to delineate SARS-CoV-2-specific anti-inflammatory molecule, we designed a hexapeptide corresponding to the Spike S1-Interacting Domain of ACE2 Receptor (SPIDAR) that inhibited the expression of proinflammatory molecules in human A549 lung cells induced by pseudotyped SARS-CoV-2, but not vesicular stomatitis virus (VSV). Accordingly, wild type (wt), but not mutated (m), SPIDAR inhibited SARS-CoV-2 spike S1-induced activation of NF-κB and expression of IL-6 and IL-1β in human lungs cells. However, wtSPIDAR remained unable to reduce activation of NF-κB and expression of proinflammatory molecules in lungs cells induced by TNFα, HIV-1 Tat, and viral double-stranded RNA mimic poly IC, indicating the specificity of the effect. The wtSPIDAR, but not mSPIDAR, also hindered the association between ACE2 and spike S1 of SARS-CoV-2 and inhibited the entry of pseudotyped SARS-CoV-2, but not VSV, into human ACE2-expressing HEK293 cells. Moreover, intranasal treatment with wtSPIDAR, but not mSPIDAR, inhibited lung activation of NF-κB, protected lungs, reduced fever, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. Therefore, selective targeting of SARS-CoV-2 spike S1-to-ACE2 interaction by wtSPIDAR may be beneficial for COVID-19.
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影响因子：
20.1
作者：
Patel VB;Zhong JC;Grant MB;Oudit GY
通讯作者：
Oudit GY
影响因子：
4.4
作者：
Jana, Malabendu;Jana, Arundhati;Pahan, Kalipada
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Pahan, Kalipada
影响因子：
6.2
作者：
Jana, Arundhati;Modi, Khushbu K.;Roy, Avik;Anderson, John A.;van Breemen, Richard B.;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
DOI：
10.1007/s11481-020-09979-8
发表时间：
2021-03
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
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作者：
Paidi RK;Jana M;Mishra RK;Dutta D;Raha S;Pahan K
通讯作者：
Pahan K
DOI：
10.1038/nrmicro2090
发表时间：
2009-03
期刊：
Nature reviews. Microbiology
影响因子：
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作者：
通讯作者：
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