Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of “old” drugs against COVID-19.

酸性鞘磷脂酶 (ASM) 将鞘磷脂裂解成高度亲脂性的神经酰胺，后者在质膜中形成大的凝胶状筏/平台。我们发现 SARS-CoV-2 使用这些平台进入细胞。由于 ASM 抑制剂、ASM 基因下调、抗神经酰胺抗体或中性神经酰胺酶降解而降低神经酰胺的量或神经酰胺阻断，可防止感染 SARS-CoV-2。添加神经酰胺可以恢复 SARS-CoV-2 的感染。许多临床批准的药物在功能上抑制 ASM，被称为 FIASMA（酸性鞘磷脂酶的功能性抑制剂）。在一项随机前瞻性研究和一项前瞻性开放标签真实世界研究中，FIASMA 氟伏沙明显示出对 COVID-19 的有益作用。回顾性和观察性研究表明，包括氟西汀在内的 FIASMA 抗抑郁药和 FIASMA 羟嗪对 COVID-19 的病程具有有利影响。ASM/神经酰胺系统为更好地了解 SARS-CoV-2 对细胞的感染以及 ASM 功能抑制剂的临床、抗病毒和抗炎作用提供了一个框架。该框架还支持开发新药或重新利用“旧”药物来对抗 COVID-19。