Producing a drug against a virus responsible for a pandemic emergency is, as we have seen with the Covid crisis, a very tough challenge against time. Today, however, thanks to artificial intelligence and supercomputers, it only takes a few hours – instead of long months of study – to identify the healing molecule that can make the difference. This is demonstrated by the case of “raloxifene”, a new weapon against Covid capable of accelerating the negativization of positives (paucisymptomatic): the anti-Covid function of this drug was discovered by the multidisciplinary consortium Exscalate4Cov (formed by 30 public and private institutions from seven countries and supported by the European Commission within the framework of the Horizon 2020 program) thanks to the supercomputing platform Exscalate created by Dompé Farmaceutici. Two studies, just published in The Lancet e Nature by researchers of the “Lazzaro Spallanzani” IRCCS of Rome, of the Temple University of Philadelphia and of Dompé.
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“The results on raloxifene published in eClinical Medicine from Lancet show a significant virological impact in terms of negative nasopharyngeal swab at day 7 in Covid-19 patients treated at home with raloxifene compared to standard of care. This randomized clinical trial confirms the in vitro data published on Nature’s Cell Death and Diseaseon the efficacy of raloxifene on cell lines experimentally infected with Sars-CoV-2 “he comments Emanuele Nicastrico-author of both studies and director of the Infectious and Tropical Diseases Unit of the Spallanzani Institute in Rome.
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The ExScalate platform can both design a new drug and find a new use for an existing drug: “We demonstrated this already in 2018, when, in a program funded by the European Commission, we carried out a simulation test of an emergency pandemic with the Zika virus, “he explains Marcello Allegretti, chief scientific officer of Dompé and co-author of the two new studies. “On that occasion, with Exscalate the structure of all the proteins expressed by the virus was reconstructed, those vital for the survival of Zika were identified, that is, the ideal targets for a drug. Then we built a library with all the approved molecules. as a drug and already successfully tested on humans, molecules which are therefore proven to be safe “.
Simulated the effect against six viral proteins
With Exscalate, the effect of all these drugs against the six Zika viral proteins identified as targets was simulated. “Generally, when you design a drug you have a single target and on this you test a library of molecules” explains Allegretti. “But thanks to the possibilities that supercomputing offers us in parallelizing this process, we were able to evaluate each drug by considering six targets at the same time, so as to identify those potentially most effective because they are able to hit the virus in more than one point”. And so in a few hours an effective molecule was found, in animal models, in stopping Zika.
And then came Sars-Cov-2
A year after this pandemic simulation, the true pandemic arrived with the Sars-CoV-2 and the Exscalate platform was able to be used in real conditions. “When not much was known about the virus yet, we relied on the structural and functional homologies between Sars-CoV-2 and the other coronaviruses already known to understand the usefulness of the individual Sars-CoV-2 proteins in cell infection. and in the replication of the virus “explains Allegretti. “And this work led us to focus on 9 viral proteins – continues Allegretti – then with the center of Leuven (Belgium) which is the most important screening test center in Europe, we tested the libraries of pharmacological molecules against 9 virus targets “.
Raloxifene works independently of variants
By finding a more effective molecule than the others, raloxifene. “Raloxifene is able to interfere with the Spike protein and also with PLpro, an important protease for the virus,” explains Allegretti. “We collaborated with Professor Arnaldo Caruso of the University of Brescia, president of the Italian Society of Virology, in the characterization of efficacy in standard models of in vitro infection, and we confirmed the hypothesis that raloxifene could slow viral replication. Particularly interesting is the fact that this ability of the drug was independent of the variants “.
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This is the result of the work that the researchers, together with colleagues from the Spallanzani Institute and the University of Brescia, carried out on both monkey and human cells. “And a multicenter clinical study, approved in Italy and in other countries, on paucisymptomatic patients in home treatment has shown that raloxifene accelerates the time of negativization of the virus, and therefore reduces the risk of complications” explains Allegretti. The fact that raloxifene was an estrogen receptor modulator seemed doubly relevant to researchers: this type of drug had in fact been studied in Asia at the time of the SARS and MERS virus epidemics, and their protective function in infections from these other coronaviruses.
Estrogen is involved (and you could guess)
“Furthermore, an involvement of estrogens in the response to the virus could also be guessed from the differences between men and women with respect to the severity of the infection. It was seen that women are more protected than men in the development of the severity of the disease” explains Allegretti. “So in addition to the direct activity of the drug on the virus, the activation of estrogen receptors could have an additional benefit.” The double action of raloxifene against Sars-CoV-2 will be detailed by researchers in a forthcoming article, but the basic mechanism seems to be established: “The Spike protein interacts with estrogen receptors: by activating them, Spike induces expression of the famous ACE2 receptor which favors the entry of the virus “explains Allegretti.
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“Raloxifene hinders this process because – in addition to blocking the Spike protein – it itself occupies the estrogen receptors, which are no longer available for the Spike protein.” This would also explain why in women there is a protective effect with respect to infection: having women a greater amount of estrogen in circulation than men, in their case it is a bit more difficult for the Spike protein to find free “estrogen receptors” “, and thus invade the cells.