Abstract: International Journal of Molecular Sciences Article Iota-Carrageenan Inhibits Replication of SARS-CoV-2 and the Respective Variants of Concern Alpha, Beta, Gamma and Delta Maria Fröba 1,† , Maximilian Große 1,† , Christian Setz 1,† , Pia Rauch 1 , Janina Auth 1 , Lucas Spanaus 1 , Jan Münch 2 , Natalia Ruetalo 3 , Michael Schindler 3 , Martina Morokutti-Kurz 4 , Philipp Graf 4 , Eva Prieschl-Grassauer 4 , Andreas Grassauer 4 and Ulrich Schubert 1, * 1 2 3 4



 Citation: Fröba, M.; Große, M.; Setz, C.; Rauch, P.; Auth, J.; Spanaus, L.; Münch, J.; Ruetalo, N.; Schindler, M.; Morokutti-Kurz, M.; et al. Iota-Carrageenan Inhibits Replication of SARS-CoV-2 and the Respective Variants of Concern Alpha, Beta, Gamma and Delta. Int. J. Mol. Sci. 2021, 22, 13202. https://doi.org/ 10.3390/ijms222413202 Academic Editor: Giovanni Maga Received: 21 October 2021 Accepted: 3 December 2021 Published: 8 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. * † Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; Maria.Carolin.Froeba@fau.de (M.F.); Maximilian.Grosse@uk-erlangen.de (M.G.); Christian.Setz@uk-erlangen.de (C.S.); Pia.Rauch@uk-erlangen.de (P.R.); Janina.Auth@fau.de (J.A.); Lucas.Spanaus@extern.uk-erlangen.de (L.S.) Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; Jan.Muench@uni-ulm.de Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, 72076 Tübingen, Germany; Natalia.Ruetalo-Buschinger@med.uni-tuebingen.de (N.R.); Michael.Schindler@med.uni-tuebingen.de (M.S.) Marinomed Biotech AG, A-2100 Korneuburg, Austria; Martina.Morokutti-Kurz@marinomed.com (M.M.-K.); Philipp.Graf@marinomed.com (P.G.); Eva.Prieschl@marinomed.com (E.P.-G.); Andreas.Grassauer@marinomed.com (A.G.) Correspondence: Ulrich.Schubert@fau.de; Tel.: +49-9131-85-26478 These authors are contributed equally to this work. Abstract: The COVID-19 pandemic continues to spread around the world and remains a major public health threat. Vaccine inefficiency, vaccination breakthroughs and lack of supply, especially in developing countries, as well as the fact that a non-negligible part of the population either refuse vaccination or cannot be vaccinated due to age, pre-existing illness or non-response to existing vaccines intensify this issue. This might also contribute to the emergence of new variants, being more efficiently transmitted, more virulent and more capable of escaping naturally acquired and vaccine-induced immunity. Hence, the need of effective and viable prevention options to reduce viral transmission is of outmost importance. In this study, we investigated the antiviral effect of iota-, lambda- and kappa-carrageenan, sulfated polysaccharides extracted from red seaweed, on SARS-CoV-2 Wuhan type and the spreading variants of concern (VOCs) Alpha, Beta, Gamma and Delta. Carrageenans as part of broadly used nasal and mouth sprays as well as lozenges have the potential of first line defense to inhibit the infection and transmission of SARS-CoV-2. Here, we demonstrate by using a SARS-CoV-2 spike pseudotyped lentivirus particles (SSPL) system and patient-isolated SARS-CoV-2 VOCs to infect transgenic A549ACE2/TMPRSS2 and Calu-3 human lung cells that all three carrageenan types exert antiviral activity. Iota-carrageenan exhibits antiviral activity with..