Amitriptyline Potently Neutralizes Distinct SARS-CoV-2 Variants Including D614G, Omicron BA.5 and Omicron XBB.1

Isabel Zydek^*Laura ThümmlerNadine BeckmannCarolin SehlMatthias SoddemannRabea GrünebergCarina ElsnerMarkus KamlerUlf DittmerOliver WitzkeStephanie KadowErich GulbinsKatrin Anne BeckerAdalbert Krawczyk^*

• Essen University Hospital, Essen, Germany

COVID-19, driven by SARS-CoV-2, continues to present a significant global health burden. Despite the availability of numerous vaccines and antivirals, preventing and treating SARS-CoV-2 infections remains an ongoing challenge, particularly due to the emergence of escape mutants and the persistence of long COVID-19 symptoms. These challenges persist in developing countries, where access to affordable and effective COVID-19 treatments remains limited. Functional inhibitors of acid sphingomyelinase (FIASMAs) have been identified as potential therapeutic agents against various viral infections, including SARS-CoV-2. Importantly, FIASMAs were shown to potently neutralize SARS-CoV-2 infections in a variant-independent manner. In this study, we evaluated the antiviral potential of amitriptyline, a commonly used antidepressant and known functional acid sphingomyelinase inhibitor, against early and newly emerged SARS-CoV-2 variants in vitro. Amitriptyline effectively inhibited cell infections by pseudotyped virus-like particles with SARS-CoV-2 spike proteins, including those with mutations in the receptor-binding domain. Furthermore, amitriptyline significantly reduced the viral replication of the clinical SARS-CoV-2 isolates D614G, Omicron BA.5 and Omicron XBB.1 in a dose-dependent manner at subtoxic concentrations. The results of this study demonstrate that amitriptyline effectively neutralizes SARS-CoV-2 across distinct variants. Further clinical trials are necessary to investigate the therapeutic potential of amitriptyline in treating SARS-CoV-2 infections and to establish its safety and efficacy in human patients.