SARS-Cov-2, The Covid-19 Pandemic Reminds us of the Antiviral Properties of Chlorpromazine

Abstract

In vitro studies have established the classic antipsychotic drug chlorpromazine (CPZ) as an effective antiviral agent against various viruses, including corona viruses [1]. Also, SARS-CoV-2, the cause of the current Covid 19 pandemic, is inhibited by CPZ [2]. CPZ is known to act on clathrin-mediated endocytosis (CME), which affects the formation of clathrin-coated pits on the plasma membrane [3]. This pathway is one of the most important entry routes of viruses, more precisely virions, into host cells. Studies on the antiviral effect of CPZ have shown that it influences different mechanisms of virus formation, including post-entry effects. CPZ belongs to the group of cationic amphiphilic drugs (CADs), which have the propensity to interact with various cell structures, especially membranes. They accumulate in intracellular compartments (acidic), such as early and late endosomes/lysosomes crucial for virus formation (e.g. particle coating, assembly or budding) [4]. In the case of corona viruses (SARS-CoV), CPZ inhibits the cell entry chiefly by CME [5]. However, CPZ it is also known to inhibit membrane fusion processes at the plasma membrane or at an intracellular location following virus uptake by endocytosis. Among them, CME and cathepsin mediated S protein cleavage are two critical steps for viral entry and infection of corona viruses (all coronaviruses are enveloped viruses with a long single-plus stranded RNA) [6]. Notably, SARS-CoV and SARS-CoV-2 use exactly the same attachment receptor (ACE2) and serine protease (TMPRSS2/S protein priming) for cell entry [7]. However, the exact nature of the viral entry is context-dependent, including the type of the virus and the type of the host cells. As mentioned above, SARS-CoV-2 utilizes the ACE2-receptor (angiotensin converting enzyme II) for viral entry into the host cells. ACE2 transcripts was originally only found in heart, kidney and testis of humans. However, it was later found that ACE2 protein expresses abundantly in the epithelia of the human lung, small intestine and brain [8].