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      Methodological notes on pandemic virus SARS-CoV-2 research

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          Abstract

          In the fight against the COVID-19 pandemic, many brilliant results have been achieved, but the thermodynamics of the novel SARS-CoV-2 coronavirus has been completely neglected. This is a serious systematic error, which can compromise the results of the entire pandemic virus SARS-CoV-2 research. In the present work, we therefore study the thermodynamics of SARS-CoV-2 in its environment, from air to endosome and endosome-independent cell entry pathways. In the study of the thermodynamics of the new coronavirus SARS-CoV-2 in air, the presence of pollen, bacteria, other viruses, spores, dust, but more particularly, that of nanoparticles of health interest at the same scale threshold as the spike proteins of the pandemic virus, such as particulate matter, cannot be neglected. This work therefore starts from a comparative study of the air environments in China and Italy, the first countries affected by the infection. Currently, a correlation between the spread of infection and pollution is still very controversial. But our paper is not concerned with this. We propose some methodological notes which lead us to the formulation of a general mathematical apparatus (an energy landscape theory), suitable to explain at the molecular level the energetic configurations of the quasi-species of the pandemic virus SARS-CoV-2 in its environment. We focus on complexes between the viral particle and other objects in its environment at the scale threshold of the spikes of the viral particle. Then, we wondered if such complexes can lead to the generation of more aggressive viral variants and how to predict their populations and energy configurations, in order to plan an adequate prophylaxis.

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          Most cited references29

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          Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

          Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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            Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

            How SARS-CoV-2 binds to human cells Scientists are racing to learn the secrets of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan et al. present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. In the context of this complex, ACE2 is a dimer. A further structure shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures provide a basis for the development of therapeutics targeting this crucial interaction. Science, this issue p. 1444
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              Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

              The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, 3CLpro), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
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                Author and article information

                Contributors
                gianluigi.zangaridelbalzo@gmail.com
                Journal
                Theory Biosci
                Theory Biosci
                Theory in Biosciences
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1431-7613
                1611-7530
                8 September 2021
                : 1-16
                Affiliations
                GRID grid.7841.a, Sapienza University of Rome, ; Rome, Italy
                Author information
                http://orcid.org/0000-0002-2730-1933
                Article
                355
                10.1007/s12064-021-00355-5
                8423596
                34494181
                733bb16f-2af3-4ab4-91ad-98e80c236c22
                © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 1 July 2020
                : 3 August 2021
                Categories
                Original Article

                Molecular biology
                covid-19,sars-cov-2,thermodynamics,environment,pollution,nanoparticles,particulate matter

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