Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing
Laura Riva, Shuofeng Yuan, Sumit K. Chanda
Abstract
The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2–4, and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19. https://www.nature.com/articles/s41586-020-2577-1
A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1–8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in nonhuman primates. Fifty-two rhesus macaques were immunized with Ad26 vectors encoding S variants or sham control and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs following SARS-CoV-2 challenge. Vaccine-elicited neutralizing antibody titres correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in nonhuman primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.
Authors
Noe B. Mercado, Roland Zahn, Frank Wegmann, Carolin Loos, Abishek Chandrashekar, Jingyou Yu, Jinyan Liu, Lauren Peter, Katherine McMahan, Lisa H. Tostanoski, Xuan He, David R. Martinez https://www.nature.com/articles/s41586-020-2607-z
Interesting approach… though a model. reading from the limitations mentioned in the article, the approach really throws open lots of challenges.
Just thinking widely, how about a simple method of installing an infra red based body temperature checking device … like the ones installed in most locations at entry point for metal detectors.
Perhaps with the entry point body temperature detection can filter out for those who may require the rapid antigen test…
May be the hand held temperature checking device can be scaled up for temperature checking. of course even the body temperature can be goofed up…
If we say that a patient is asymptomatic, this means that the virus is replicating inside the patient but no symptoms are seen.
So, does this mean that the person is left unharmed?
If we have a senior citizen with co-morbidity, and she/he is seen to be asymptomatic carrier of the disease, then what are their survival chances (if so)?
As far as I could gather form the papers posted here, asymptomatic persons do not show any damage.
However one of my doctor friends states that it will take about a year and a half to gather sufficient data and analyse the same.
But,the person is spreading the virus right?
That is why we call them asymptomatic carriers.
So if the virus is being spread through that person, it means that the virus must be replicating inside him/her. This is the case with the symptomatic patients too (the virus is replicating there too)!!
But the only difference seen here is of the health/immunity.
The symptomatic one’s health is affected and as @jtd confirmed, “asymptomatic persons do not show any damage”.
Then what does this indicate?
Are these asymptomatic patients a reservoir of the SARS-CoV2?
(No conclusions are being drawn here)
Indeed. They are reservoirs until the infection is removed by the body’s immuno system.
However this WHO article raises some doubts about asymptomatic patients remaing unaffected as the researchers have not stated followup methodology.
For a layered cloth mask, layered handkerchief mask, layered dupatta mask can also be decontaminated after hot water wash with soap, and then ironing it for heat drying. We use this method
A simpler ‘home’ version of this test involves sitting between a general light source, like sunlight, and the camera.
A large home mirror provides the backdrop for the illuminated particles (droplets).
This doesn’t yield particle count or size, but it gives a home mask maker a fairly good sense of judgment about whether the mask provides a reasonable quality of droplet block.
We often hear about monkeys, bats, and birds as reservoirs of diseases. Since humans are also animals, we may also be reservoirs of some diseases, right? What do we know about human bodies as reservoirs of any diseases, other than viral reservoirs of messages we spread?
The coronavirus 2019 (COVID-19) respiratory disease is caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which uses the enzyme ACE2 to enter human cells. This disease is characterized by important damage at a multi-organ level, partially due to the abundant expression of ACE2 in practically all human tissues. However, not every organ in which ACE2 is abundant is affected by SARS-CoV-2, which suggests the existence of other multi-organ routes for transmitting the perturbations produced by the virus. We consider here diffusive processes through the protein–protein interaction (PPI) network of proteins targeted by SARS-CoV-2 as an alternative route. We found a subdiffusive regime that allows the propagation of virus perturbations through the PPI network at a significant rate. By following the main subdiffusive routes across the PPI network, we identify proteins mainly expressed in the heart, cerebral cortex, thymus, testis, lymph node, kidney, among others of the organs reported to be affected by COVID-19.
