Good News: Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Good news  - 

A paper entitled "Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production" just was published. SARS-CoV-2 is another name for the coronovirus (COVID-19).
https://www.biorxiv.org/content/10.1101/2020.04.04.020925v1

This work was performed by scientists from the Centro de Desenvolvimento Tecnológico em Saúde (CDTS) of FIOCRUZ. My friend, Carlos Morel, is Director of this Center.

This drug has been approved previously for other retroviral diseases.

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Natalia Fintelman-Rodrigues, Carolina Q. Sacramento, Carlyle Ribeiro Lima, Franklin Souza da Silva, André C. Ferreira, Mayara Mattos, Caroline S. de Freitas, Vinicius Cardoso Soares, Suelen da Silva Gomes Dias, Jairo R. Temerozo, Milene Miranda, Aline R. Matos, Fernando A. Bozza, Nicolas Carels, Carlos Roberto Alves, Marilda M. Siqueira, Patrícia T. Bozza,  View ORCID ProfileThiago Moreno L. Souza

doi: https://doi.org/10.1101/2020.04.04.020925

This article is a preprint and has not been certified by peer review [what does this mean?].

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the ongoing pandemic of 2019 CoV disease (COVID-19), which is already responsible for far more deaths than were reported during the previous public health emergencies of international concern provoked by two related pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of any clinically approved drug that could be repurposed to combat COVID-19 would allow the rapid implementation of potentially life-saving procedures to complement social distancing and isolation protocols. The major protease (Mpro) of SARS-CoV-2 is considered a promising target for drug interventions, based on results from related CoVs with lopinavir (LPV) an HIV protease inhibitor, that that can inhibit the Mpro of 2002 SARS-CoV. However, limited evidence exists for other clinically approved anti-retroviral protease inhibitors that may bind more efficiently to Mpro from SARS-CoV-2 and block its replication. Of high interest is atazanavir (ATV) due to its documented bioavailability within the respiratory tract, which motivated our evaluation on its ability to impair SARS-CoV-2 replication through a series of in vitro experiments. A molecular dynamic analysis showed that ATV could dock in the active site of SARS-CoV-2 Mpro with greater strength than LPV and occupied the substrate cleft on the active side of the protease throughout the entire molecular dynamic analysis. In a cell-free protease assay, ATV was determined to block Mpro activity at a concentration of 10 μM. Next, a series of assays with in vitro models of virus infection/replications were performed using three cell types, Vero cells, a human pulmonary epithelial cell line and primary human monocytes, which confirmed that ATV could inhibit SARS-CoV-2 replication, alone or in combination with ritonavir (RTV). In addition, the virus-induced levels of IL-6 and TNF-α were reduced in the presence of these drugs, which performed better than chloroquine, a compound recognized for its anti-viral and anti-inflammatory activities. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.

A Suggestion for testing for the Virus

I just heard by accident the daily campaign rally by the orange monster. He emphasized that "we" had done over 1 million tests for the virus. First of all I really do not believe anything he says. Second, one million out of a country of 327 million people is not very statistically meaningful. 

It suddenly hit me what can be done. It is so simple, First divide the entire country into a small number of random lots. Then test every single person in those lots. If this is feasible then scale up and do a larger number of randomly chosen lots. The statisticians and people who do the virus infection modeling will be very excited to finally have sufficient meaningful data. They do not have to test the entire country, just a sufficient number of lots of the same size and they can scale up. Of course the choice of lots must avoid totally uninhabited regions, but otherwise random.

You see - if they get enough numbers of people infected, uninfected and infected with symptoms, and of course the people who died from the virus infection - then the analysis should be essentially the same as doing the entire country!

Note added 4/18/2020
I now feel that my proposal was very naive. The distribution of people in the US is not 2 dimensional but is 3 dimensional. The suggestion did not take into account large cities with multistory apartments and hotels. It is not obvious just how to handle these situations. For example one could define a "lot" as being a  vertical slice through a multistory structure or simply one floor and one apartment. In any case the proposal was not well thought out.