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Effects of Basic Amino Acids and Their Derivatives on SARS-Cov-2 and Influenza-A Virus Infection

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Effects of Basic Amino Acids and Their Derivatives on SARS-Cov-2 and Influenza-A Virus Infection viruses Article Effects of Basic Amino Acids and Their Derivatives on SARS-CoV-2 and Influenza-A Virus Infection Ivonne Melano 1 , Li-Lan Kuo 2, Yan-Chung Lo 3, Po-Wei Sung 4, Ni Tien 5,6 and Wen-Chi Su 1,2,7,* 1 Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan; [email protected] 2 Research Center for Emerging Viruses, China Medical University Hospital, Taichung 40402, Taiwan; [email protected] 3 Sinphar Pharmaceutical Co., Ltd., Sinphar Group, Yilan 269, Taiwan; [email protected] 4 School of Medicine, China Medical University, Taichung 40402, Taiwan; [email protected] 5 Department of Laboratory Medicine, China Medical University Hospital, Taichung 40402, Taiwan; [email protected] 6 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan 7 International Master’s Program of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan * Correspondence: [email protected] Abstract: Amino acids have been implicated with virus infection and replication. Here, we demon- strate the effects of two basic amino acids, arginine and lysine, and their ester derivatives on infection of two enveloped viruses, SARS-CoV-2, and influenza A virus. We found that lysine and its ester derivative can efficiently block infection of both viruses in vitro. Furthermore, the arginine ester derivative caused a significant boost in virus infection. Studies on their mechanism of action revealed that the compounds potentially disturb virus uncoating rather than virus attachment and endosomal Citation: Melano, I.; Kuo, L.-L.; Lo, acidification. Our findings suggest that lysine supplementation and the reduction of arginine-rich Y.-C.; Sung, P.-W.; Tien, N.; Su, W.-C. Effects of Basic Amino Acids and food intake can be considered as prophylactic and therapeutic regimens against these viruses while Their Derivatives on SARS-CoV-2 and also providing a paradigm for the development of broad-spectrum antivirals. Influenza-A Virus Infection. Viruses 2021, 13, 1301. https://doi.org/ Keywords: SARS-CoV-2; COVID-19; influenza A virus; lysine; arginine; disease prevention; 10.3390/v13071301 antiviral therapy Academic Editor: Kenneth Lundstrom 1. Introduction Received: 14 May 2021 Coronavirus disease 2019 (COVID-19) is a global pandemic and has burdened the Accepted: 30 June 2021 world since late 2019. With a reproductive number of around 3.28 [1], severe acute res- Published: 4 July 2021 piratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, has infected approximately 158 million people worldwide; while 3.29 million individuals have Publisher’s Note: MDPI stays neutral succumbed to the virus by April 2021 (Source: World Health Organization). Thus far, there with regard to jurisdictional claims in are seven coronaviruses (CoVs) that can infect humans, and only three CoVs, including published maps and institutional affil- SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, iations. cause severe symptoms and even death [2]. Recovered patients from SARS-CoV, which shares 82.45% homology with SARS-CoV-2 [3], were incapable of fully gaining back their lung function even after two years post-infection [4]. COVID-19, however, has a lower mortality rate yet shows similar clinical manifestations as SARS-CoV infection. Moreover, Copyright: © 2021 by the authors. it has reports show that even after months of being cleared of SARS-CoV-2 viral antigen, Licensee MDPI, Basel, Switzerland. people (called “long haulers”) were still experiencing the severe effects of COVID-19, such This article is an open access article as extreme fatigue and brain fog [5]. Currently, no effective treatment against SARS-CoV-2 distributed under the terms and is available. conditions of the Creative Commons Attribution (CC BY) license (https:// The influenza A virus (IAV), a causative agent of the common flu, is another respiratory creativecommons.org/licenses/by/ virus that causes annual epidemics and recurring pandemics that threaten public health 4.0/). and the global economy. Though vaccines and antivirals against IAV are in development Viruses 2021, 13, 1301. https://doi.org/10.3390/v13071301 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 14 Viruses 2021, 13, 1301 2 of 13 health and the global economy. Though vaccines and antivirals against IAV are in devel- opment and production, its rapid evolution still poses a cause for concern [6]. Further- more,and production,it has a high its rate rapid of evolutionco-infection still with poses SARS-CoV-2 a cause for concern [7]. Pre-infection [6]. Furthermore, of IAV itaug- has a mentshigh SARS-CoV-2 rate of co-infection infectivity, with SARS-CoV-2increases SARS-CoV-2 [7]. Pre-infection viral load, of IAV and augments induces more SARS-CoV-2 severe lunginfectivity, pathogenic increases changes SARS-CoV-2 [8,9]. viral load, and induces more severe lung pathogenic changesBoth of [8 ,9these]. enveloped viruses enter the cells via receptor-mediated endocytosis. Their virusBoth surface of these proteins enveloped, SARS-CoV-2 viruses enter Spike the protein cells via and receptor-mediated IAV Hemagglutinin endocytosis. (HA), recognizeTheir virus andsurface bind to proteins,the cell surface SARS-CoV-2 receptors Spike ACE2 protein and sialic and acid-containing IAV Hemagglutinin receptors, (HA), respectively.recognize and The bind host to cell the then cell engulfs surface receptorsthe virus ACE2by endocytosis. and sialic During acid-containing endocytosis, receptors, the endosomesrespectively. have The low host pH cell (pH then 6.5-4.8) engulfs that the trigge virusrs the by endocytosis.viral attachment During proteins endocytosis, to induce the conformationalendosomes have changes low pH of (pHfusing 6.5-4.8) with thatthe endosomal triggers the membrane viral attachment and proceed proteins to to uncoat induce andconformational release its viral changes genome of into fusing the with cytoplasm the endosomal [10–15]. Another membrane cell and entry proceed mechanism to uncoat of SARS-CoV-2and release is its by viral plasma genome membrane into the fusion cytoplasm, wherein [10–15 TMPRSS2,]. Another a cell cell entry surface mechanism protease, of cleavesSARS-CoV-2 SARS-CoV-2 is by plasmaSpike to membrane promote viral fusion, and wherein cell membra TMPRSS2,ne fusion; a cell now surface permitting protease, SARS-CoV-2cleaves SARS-CoV-2 to release Spikeits viral to genome promote into viral the and cytoplasm cell membrane [16–18]. fusion; now permitting SARS-CoV-2A high mutation to release rate its is viral a significant genome challenge into the cytoplasm in developing [16–18 antivirals]. against RNA viruses.A These high mutationmutations rate may is benefit a significant virus challengelife cycles, in such developing as evading antivirals immune against response, RNA increasingviruses. Thesevirus mutationstransmissibility, may benefit or enhancing virus life pathogenesis. cycles, such Hence, as evading the need immune to discover response, broad-spectrumincreasing virus antiviral transmissibility, agents for or current enhancing and pathogenesis.future virus diseases Hence, is the undisputed need to discover [19]. Previousbroad-spectrum research has antiviral shown agents that the for amino current acids and futurearginine virus and diseases lysine play is undisputed roles in virus [19 ]. infectionPrevious and research replication has shown[20–26]. that Lysine, the amino an essential acids amino arginine acid, and has lysine long play been roles prescribed in virus againstinfection herpes and simplex replication virus [20 (HSV)–26]. Lysine, infection an essential[25–27]. A amino high acid,lysine/arginine has long been ratio prescribed has de- creasedagainst HSV herpes plaque simplex formation virus in (HSV) vitro infection[22–24]. Clinical [25–27]. trials A high have lysine/arginine exhibited a reduction ratio has decreased HSV plaque formation in vitro [22–24]. Clinical trials have exhibited a reduction of recurrent HSV attacks, fewer healing days, and milder symptoms during a six-month of recurrent HSV attacks, fewer healing days, and milder symptoms during a six-month period of L-lysine monochloride therapy [27,28]. Therefore, we investigated whether period of L-lysine monochloride therapy [27,28]. Therefore, we investigated whether these these basic amino acids could also affect SARS-CoV-2 and IAV infection. In this study, we basic amino acids could also affect SARS-CoV-2 and IAV infection. In this study, we used an used an in vitro system to evaluate the effects of lysine, arginine, and their derivatives, L- in vitro system to evaluate the effects of lysine, arginine, and their derivatives, L-Arginine Arginine methyl ester dihydrochloride (Arg-ester), and L-Lysine ethyl ester dihydrochlo- methyl ester dihydrochloride (Arg-ester), and L-Lysine ethyl ester dihydrochloride (Lys- ride (Lys-ester) (Figure 1), on SARS-CoV-2 and IAV infection. ester) (Figure1), on SARS-CoV-2 and IAV infection. FigureFigure 1. 1.ChemicalChemical structure structure of ofthe the compounds. compounds. 2. Materials and Methods 2. Materials and Methods 2.1. Cells 2.1. Cells HEK293T cells were grown in DMEM (Gibco), supplemented with 10% FBS and antibioticsHEK293T (100 cells U/mL were penicillin grown in G DMEM and 100 (Gibco),µg/mL supplemented streptomycin). with Huh7 10% cells FBS were and grown an- tibioticsin the same(100 U/mL media penicillin but with addedG and 1%100 non-essentialµg/mL streptomycin). amino acids. Huh7 H1650 cells cellswere were grown grown in thein same RPMI media (Gibco), but supplemented with added 1% with non-essent 10% FBSial (Hyclone) amino acids. and H1650 antibiotics. cells were A549 grown cells were in RPMImaintained (Gibco), in supplemented an F-12K medium with (Gibco), 10% FBS supplemented (Hyclone) and with antibiotics. 10% FBS and A549 antibiotics. cells were All ◦ maintainedcells were in cultured an F-12K at 37mediumC and (Gibco), 5% CO 2supplemented. with 10% FBS and antibiotics. All cells were cultured at 37 °C and 5% CO2.
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