The biosynthesis of host lipids and/or lipid droplets (LDs) has been studied extensively as a putative therapeutic target in diverse viral infections. However, directly targeting the LD lipolytic catabolism in virus-infected cells has not been widely investigated. Here, we show the linkage of the LD-associated lipase activation to the breakdown of LDs for the generation of free fatty acids (FFAs) at the late stage of diverse RNA viral infections, which represents a broad-spectrum antiviral target. Dysfunction of membrane transporter systems due to virus-induced cell injury results in intracellular malnutrition at the late stage of infection, thereby making the virus more dependent on the FFAs generated from LD storage for viral morphogenesis and as a source of energy. The replication of SARS-CoV-2 and influenza A virus (IAV), which is suppressed by the treatment with LD-associated lipases inhibitors, is rescued by supplementation with FFAs. The administration of lipase inhibitors, either individually or in a combination with virus-targeting drugs, protects mice from lethal IAV infection and mitigates severe lung lesions in SARS-CoV-2-infected hamsters. Moreover, the lipase inhibitors significantly reduce proinflammatory cytokine levels in the lungs of SARS-CoV-2- and IAV-challenged animals, a cause of a cytokine storm important for the critical infection or mortality of COVID-19 and IAV patients. In conclusion, the results reveal that lipase-mediated intracellular LD lipolysis is commonly exploited to facilitate RNA virus replication and furthermore suggest that pharmacological inhibitors of LD-associated lipases could be used to curb current COVID-19- and future pandemic outbreaks of potentially troublesome RNA virus infection in humans.
The reactiono fa lkynyl carboxylic acids, glyoxylic acid derivatives, and amines in the presence of ac opper catalyst afforded the corresponding propargyl amines in good yields. The alkynyl carboxylic acid of this coupling reaction shows similarr eactivity to that of at erminal alkyne, and the reactivityo ft he glyoxylic acid is almost identicalt ot hat of an aldehyde. When 2-aminopyridine was employed as the amine source, imidazopyridine derivatives weref ormedi n good yields.Scheme1.Different approaches to the synthesis of propargyl amines.[a] J.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.
Amino-substitutedp olycyclic aromatic hydrocarbons were obtained by the reaction between aryl alkynyl carboxylic acids and amines in the presence of ac opper catalyst. The hydrocarbonsw ere obtained in good yield with-out the need to isolate the 1,4-diaryl-1,3-butadiyne intermediate. The best result was obtained using ac ombination of CuCl and Cu(OTf) 2 ,a nd the reactions of cyclic anda cyclic secondary amines afforded the desired products.Scheme1.Synthesis of amino-substitutednaphthalenes.[a] J.
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