Initially, the pandemic COVID-19, caused by SARS-CoV-2, was considered to be an exclusive lung disease, eventually leading to serious respiratory symptoms 1 . In the meantime, accumulating experimental and clinical studies have suggested that SARS-CoV-2 may also cause lesions in the kidneys, heart, brain, and gastrointestinal and endocrine organs [2][3][4][5][6][7] . SARS-CoV-2 tropism towards distinct tissues is governed by cellular factors expressed on target cells such as the viral entry receptor angiotensin-converting enzyme 2 (ACE2) 8 and the transmembrane serine protease 2 (TMPRSS2) 8 . ACE2 messenger RNA 9-13 and protein 12-14 expression within the islets of Langerhans has been reported, but not yet been shown, to allow SARS-CoV-2 entry 9,12,15 . Diabetes mellitus presents Janus like in 16 ): first, pre-existing diabetes is a highly prevalent comorbidity observed in 11-22% of patients and as such increases the risk of a severe disease, requiring more intense interventions and increasing mortality [17][18][19][20][21][22] . Second, SARS-CoV-2 infection seems to affect the exocrine pancreas, manifesting as pancreatitis in 32.5% of critically ill patients 23 , and pancreatic enlargement and abnormal amylase or lipase levels in 7.5-17% of patients 9,22 . Third, metabolic dysregulation has been observed in patients with COVID-19 as:(1) increased hyperglycaemia in patients with type 2 diabetes 24 ; (2) ketoacidosis in 2-6.4% of diabetic and non-diabetic patients 18,25 ; and (3), in case studies reporting ketoacidosis on SARS-CoV-2 infection, accompanied by (4) new-onset type 1 diabetes mellitus (T1DM) in the absence of autoantibodies [26][27][28] . In a cohort study of patients with diabetes, hyperglycaemia was reported in more than 50% of all cases, and almost a third experienced diabetic ketoacidosis 29 . Finally, a multicentre study found an 80% increase of new-onset T1DM in children during the COVID-19 pandemic 30 . In accordance, a recent meta-analysis summarizes that severe SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) can restrict viral pathogens, but pro- and anti-viral activities have been reported for coronaviruses. Here, we show that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. However, endogenous IFITM expression supports efficient infection of SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral infection. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. IFITM-derived peptides and targeting antibodies inhibit SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are cofactors for efficient SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and are potential targets for therapeutic approaches.

SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.

No abstract

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the “phosphate tweezer” CLR01, a “carboxylate tweezer” CLR05, and a “phosphate clip” PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.