closed virus access in human cells

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New molecular approaches to the treatment of Covid-19 infection: researchers from the Federico II University of Naples and the University of Perugia identify endogenous molecules capable of preventing the entry of the virus into human cells.

The professor’s research groups Stefano Fiorucci (Gastroenterology of the Department of Surgical and Biomedical Sciences of the University of Perugia) and of Dr. Bruno Catalanotti and the teacher Angela Zampella (both belonging to the Pharmacy department of the University of Naples Federico II) are the co-authors of the research just published in pre-print on the site BioRxiv which reports the identification of new molecular targets capable of interfering with the entry mechanism of Covid-19 into the target cells.

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The study combined computational approaches from the group of synthetic chemistry and molecular biology and also involved the microbiology and infectious disease groups of the University of Perugia.

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The study was conducted through a first in silico (computational) screening of libraries of natural substances and drugs approved for clinical use by the Food and Drug Administation and allowed the identification of functional “pockets” in the receptor binding domain structure of the Spike protein of the virus. The further characterization of these structures has led to the surprising discovery of the existence of endogenous substances capable of interfering in the binding of spike’s Rbd with the Ace2 receptor (Angiotensin Converting Enzyme 2).

The endogenous molecules described in this work are steroid in nature and some of them are bile acids, or substances produced in the liver and intestines by cholesterol metabolism.

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Primary bile acids (i.e. those generated in the liver) bind, although with low efficiency, Spike’s Rbd, while bile acids currently used in therapy (ursodessocolic acid) and their metabolites inhibit the bond between Spike’s Rbd and Ace2 of approximately 50%. Semi-synthetic bile acids also possess this ability.

Like endogenous bile acids, natural substances, such as some triterpenoids (betulinic acid, oleanolic acid and glycyrrhizic acid), are able to bind Spike’s Rbd and are moderately effective in reducing the bond with Ace2.

Finally, drugs and their steroid-based metabolites (e.g. potassium carnenoate) interfere with the bond between Spike and Ace2.

The work was supported by a company research grant Bar Pharmaceuticals SrL to the two universities and the research results have been the subject of an Italian patent application.

«Since the coronavirus disease caused by the Covid-19 virus spread in early 2020 – explain the promoters of the research – an unprecedented effort has been made to identify new treatments capable of stopping the progression of Covid-19. This effort has involved research centers around the world allowing for rapid identification of the molecular mechanisms that allow the virus to enter the host’s target cells and then replicate. Fundamental studies by various research groups have shown that the mutation of the Spars protein of Sars-Cov2 confers affinity to the virus for a complementary protein sequence localized on the carboxypeptidase region of the human Ace 2 receptor (Angiotensin Converting Enzyme 2), a receptor that metabolizes l angiotensin II to generate angiotensin 1-7. Bonding with the receptor is necessary for another enzyme, Tmprss2, to separate the S1 sequence from Spike’s S2. Once exposed, the S2 portion of the protein engages the host cell membrane, initiating the molecular mechanism of entry of the virus. In short, the Sars-Cov2 virus pirates a human receptor. In investigating the mechanism of action of the virus, however, we realized that the organism is able to put in place non-immunological countermeasures, i.e. endogenous molecules not deriving from the immune response, which by binding some regions located in Spike’s CBD prevent / they reduce the binding to Ace2, preventing the virus from entering the target cells. If the virus then functions as a pirate who uses a human receptor to enter a target cell, our body also has defensive mechanisms that can reduce the virus’ ability to bind its target receptor. On behalf of all the authors, we would like to underline that the result achieved is the result of a work that lasted a few months and that continued uninterruptedly throughout the whole phase of the Covid-19 pandemic and in which doctoral, post- doc and doctors in training from the two universities. The current results are a demonstration of how the system of university biomedical research in Italy is able to produce useful results and to give timely solutions to complex problems. From the point of view of Covid-19 therapy, it seems probable that the developed approach will not allow to treat patients with severe respiratory distress pictures, because the antibodies of the hyperimmune serum obtained from patients cured by Covid-19 are much more effective in inhibit the bond between Spike and Ace2 of the molecules we discovered. However, the substances studied and others that we hope to be able to investigate shortly, are in some cases endogenous molecules or drugs already widely used for many years, with a consolidated safety profile, which would allow their immediate use in patients with Covid-19 . This approach, therefore, could allow to drastically reduce the times for the execution of clinical trials. The study is prodromal to the drafting of a therapeutic protocol that will be proposed to the attention of Aifa “. © RESERVED REPRODUCTION



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