发现COVID-19的治疗方法是当务之急。除了高通量筛选的化合物,可以根据其已知的作用机制和当前对SARs-CoV-2生命周期的理解来确定候选人.使用这种方法,质子泵(PPI)和钠氢交换抑制剂(NHEI)的出现,因为它们有可能抑制可以促进疾病进展的细胞外囊泡(EV;外泌体和/或微囊泡)的释放,并直接破坏SARs-CoV-2的发病机制。如果电动汽车像其他病毒一样加剧了SARs-CoV-2感染,那么通过PPI/NHEI抑制EV释放应该是有益的。这些药物抑制EV释放的潜在机制仍然不确定,但可能涉及干扰内体pH,尤其是形成腔内囊泡(新生外泌体)的多囊泡体。此外,PPI可能会抑制涉及EV生物发生的运输机制的内体分选复合物。通过扰乱内吞囊泡的pH,PPI/NHEI还可以阻止病毒与内体膜融合所必需的组织蛋白酶对SARs-CoV-2刺突蛋白的切割。尽管肺上皮细胞可能主要依赖质膜丝氨酸蛋白酶TMPRSS2进入细胞,PPI/NHEI在表达ACE2的细胞中可能是有效的,其中病毒内吞是主要的或有贡献的进入途径。这些药物也可能扰乱内质网-高尔基体中间区和高尔基体区室的pH,从而分别潜在地破坏刺突蛋白/ACE2的病毒组装和糖基化。一个警告,然而,在一项研究中报道了在增加高尔基体pH值后,促进而不抑制禽传染性支气管炎CoV的发病机理。包膜蛋白衍生的病毒体蛋白有助于感染SARs-CoV的小鼠的肺水肿形成。如果SARs-CoV-2发生类似的发病机制,则用NHEI阻断这些通道可以改善疾病的发病机制。为了确定它们的潜在功效,在SARs-CoV-2感染的不同阶段,PPIs/NHEI需要在细胞和动物模型中进行评估。如果它们被证明是治疗性的,在严重细胞因子释放综合征发病前给药可能实现最大的益处.
Discovering therapeutics for COVID-19 is a priority. Besides high-throughput screening of compounds, candidates might be identified based on their known mechanisms of action and current understanding of the SARs-CoV-2 life cycle. Using this approach, proton pump (PPIs) and sodium-hydrogen exchanger inhibitors (NHEIs) emerged, because of their potential to inhibit the release of extracellular vesicles (EVs; exosomes and/or microvesicles) that could promote disease progression, and to directly disrupt SARs-CoV-2 pathogenesis. If EVs exacerbate SARs-CoV-2 infection as suggested for other viruses, then inhibiting EV release by PPIs/NHEIs should be beneficial. Mechanisms underlying inhibition of EV release by these drugs remain uncertain, but may involve perturbing endosomal pH especially of multivesicular bodies where intraluminal vesicles (nascent exosomes) are formed. Additionally, PPIs might inhibit the endosomal sorting complex for transport machinery involved in EV biogenesis. Through perturbing endocytic vesicle pH, PPIs/NHEIs could also impede cleavage of SARs-CoV-2 spike protein by cathepsins necessary for viral fusion with the endosomal membrane. Although pulmonary epithelial cells may rely mainly on plasma membrane serine protease TMPRSS2 for cell entry, PPIs/NHEIs might be efficacious in ACE2-expressing cells where viral endocytosis is the major or a contributing entry pathway. These pharmaceutics might also perturb pH in the endoplasmic reticulum-Golgi intermediate and Golgi compartments, thereby potentially disrupting viral assembly and glycosylation of spike protein/ACE2, respectively. A caveat, however, is that facilitation not inhibition of avian infectious bronchitis CoV pathogenesis was reported in one study after increasing Golgi pH. Envelope protein-derived viroporins contributed to pulmonary edema formation in mice infected with SARs-CoV. If similar pathogenesis occurs with SARs-CoV-2, then blocking these channels with NHEIs could ameliorate disease pathogenesis. To ascertain their potential efficacy, PPIs/NHEIs need evaluation in cell and animal models at various phases of SARs-CoV-2 infection. If they prove to be therapeutic, the greatest benefit might be realized with the administration before the onset of severe cytokine release syndrome.