Disparate viral pandemics from COVID19 to monkeypox and beyond: a simple, effective and universal therapeutic approach hiding in plain sight.
Disparate viral pandemics from COVID19 to monkeypox and beyond: a simple, effective and universal therapeutic approach hiding in plain sight.
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DOI：
10.3389/fimmu.2023.1208828
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
抗病毒治疗领域专注于covid - 19，这是正确的，因为在美国疫情最严重的12个月里，在2020/2021年的部分时间里，死亡人数接近100万。一种名为SARS-CoV2的冠状病毒是致病病毒。以mRNA作为病毒刺突蛋白的诱导剂，通过分子生物学方法开发疫苗在降低死亡率和发病率方面发挥了重要作用。在住院治疗水平上，抗病毒药物对已确诊的感染没有多大价值。因此，目前的重点是大约头五天的早期症状感染。辉瑞公司的药物paxlovid由SARS-CoV2 Mpro酶的拟肽蛋白酶抑制剂尼马特利韦（nirmatrelvir）和抑制尼马特利韦降解的利托那韦（ritonavir）组成，是目前FDA推荐的早期covid - 19治疗药物。没有证据表明paxlovid对其他多种病毒（如流感病毒、痘病毒以及许多呼吸道病毒）具有广泛的抗病毒活性。尽管I型干扰素（ifn）在细胞培养物和covid - 19早期感染中对SARS-CoV2有效，但它们尚未被广泛推荐作为covid - 19的治疗方法。我们基于IFN信号传导的非规范模型，包括IFN的c端，开发了I型和II型IFN的稳定的肽模拟物。我们还鉴定了细胞内检查点抑制剂的两个成员，称为细胞因子信号抑制因子（SOCS）， SOCS1和SOCS3 (SOCS1/3)，并表明它们是病毒诱导的内在毒力蛋白，具有抗IFN信号酶JAK2和TYK2的活性。我们开发了一种基于JAK2激活环的拟肽拮抗剂，用于对抗SOCS1/3，并表明它与IFN模拟物协同作用，具有强大的广谱抗病毒活性，而没有完整IFN分子的毒性。与目前使用的抗病毒药物相比，IFN模拟物和SOCS1/3拮抗剂在针对多种病毒的安全性和效力方面应该具有优势。
The field of antiviral therapeutics is fixated on COVID19 and rightly so as the fatalities at the height of the pandemic in the United States were almost 1,000,000 in a twelve month period spanning parts of 2020/2021. A coronavirus called SARS–CoV2 is the causative virus. Development of a vaccine through molecular biology approaches with mRNA as the inducer of virus spike protein has played a major role in driving down mortality and morbidity. Antivirals have been of marginal value in established infections at the level of hospitalization. Thus, the current focus is on early symptomatic infection of about the first five days. The Pfizer drug paxlovid which is composed of nirmatrelvir, a peptidomimetic protease inhibitor of SARS–CoV2 Mpro enzyme, and ritonavir to retard degradation of nirmatrelvir, is the current FDA recommended treatment of early COVID19. There is no evidence of broad antiviral activity of paxlovid against other diverse viruses such as the influenza virus, poxviruses, as well as a host of respiratory viruses. Although type I interferons (IFNs) are effective against SARS–CoV2 in cell cultures and in early COVID19 infections, they have not been broadly recommended as therapeutics for COVID19. We have developed stable peptidomimetics of both types I and II IFNs based on our noncanonical model of IFN signaling involving the C-terminus of the IFNs. We have also identified two members of intracellular checkpoint inhibitors called suppressors of cytokine signaling (SOCS), SOCS1 and SOCS3 (SOCS1/3), and shown that they are virus induced intrinsic virulence proteins with activity against IFN signaling enzymes JAK2 and TYK2. We developed a peptidomimetic antagonist, based on JAK2 activation loop, against SOCS1/3 and showed that it synergizes with the IFN mimetics for potent broad spectrum antiviral activity without the toxicity of intact IFN molecules. IFN mimetics and the SOCS1/3 antagonist should have an advantage over currently used antivirals in terms of safety and potency against a broad spectrum of viruses.
影响因子：
7
作者：
通讯作者：
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影响因子：
13
作者：
Aricò E;Bracci L;Castiello L;Urbani F;Casanova JL;Belardelli F
通讯作者：
Belardelli F