Omicronwhich is yours lair? The mechanism by which Sars-CoV-2 builds its lair inside the organism has been revealed. A discovery that suggests a new potential drug target for future anti-Covid molecules. The Institute announces it Telethon of genetics and medicine (Tigem) of Pozzuoli the research group led by Antonella De Matteis, with a study published in Nature. The work, in addition to the Telethon Foundation, was supported by the Campania Region and the Ministry of University and Research. Using cellular models of rare genetic diseases, the researchers elucidated a still poorly understood aspect of coronavirus replication.
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“This work confirms once again how rare genetic diseases are an extraordinary model for studying basic cellular mechanisms that could therefore also play an important role in common diseases such as Covid 19”, highlights Andrea Ballabio, director of the Telethon Institute of Genetics and Medicine (Tigem) of Pozzuoli. “Since the onset of the coronavirus pandemic, we have wondered how to put our skills at the service of this global health emergency, to better clarify the behavior of the new virus, in particular how it exploits the host cell to its advantage”, explains Antonella De Matteis , who directs the cell biology program of the Telethon Institute of Genetics and Medicine (Tigem) of Pozzuoli and is full professor of cell biology at the Federico II University of Naples. «The interest of our laboratory – he continues – is focused on the study of two important intracellular districts which are the endoplasmic reticulum and the Golgi complex. Over the years we have tried to understand how mutations in genes that cause diseases such as Lowe’s syndrome, Fabry disease or a form of amyotrophic lateral sclerosis (Sla8) interfere with the organization of these districts and how the dysfunction of these districts leads to the manifestations of the disease “.
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Together with his team, De Matteis has developed cellular systems that reproduce the defects responsible for these genetic diseases and has also optimized them in order to search for correctors of cellular dysfunctions induced by mutation of the disease genes, highlights a note from Telethon. Thanks to the basic research work conducted over the years on these disease models, the researchers found themselves ready to address one of the many obscure points concerning the strategy implemented by Sars-CoV-2, as well as by other coronaviruses. , to make the most of the host cell’s resources. “Immediately after entering our cells, Sars-CoV-2 sheds its coating, consisting of the now famous spike protein target of vaccines and two other proteins called M and E – explains De Matteis – Before starting to reproduce, the virus builds a sort of den by exploiting the membranes of the host cell, in particular those of the endoplasmic reticulum, an important structure for various cellular activities, including the synthesis of proteins. In this niche the virus it can replicate its own RNA-based genetic heritage undisturbed, safe from the control systems of the host cell: a bit like a mother protecting her young from predators ».
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Until now, the mechanism by which the ‘den’ is built was almost unknown. The Tigem researchers have discovered that three proteins of the virus are important for this process: two – called Nsp3 and Nsp4 – form the real lair, made of round double-membrane vesicles within which RNA replicates, while a third – called Nsp6 – guarantees the connection with the structure from which the bricks to build the lair, the endoplasmic reticulum, arrive.
“We have to imagine a very narrow tunnel, which allows only the fats needed to enlarge the burrow to pass but which prevents the passage of cellular proteins dangerous for the new copies of viral Rna – adds De Matteis – Another important aspect is that some variants of Sars-CoV-2 believed to be much more infectious, including omicron, have a mutated form of the Nsp6 protein, which is able to make even tighter tunnels and, thanks to this, to replicate faster. In other words, we have identified a factor that favors the replication of the virus, but which we can perhaps try to neutralize pharmacologically: in fact, we have identified small molecules capable of interfering with Nsp6 and reducing its ability to form tight tunnels. A potential pharmacological target – he concludes – for new antivirals that we hope to better characterize in the near future ».