Welcome to DU!
The truly grassroots left-of-center political community where regular people, not algorithms, drive the discussions and set the standards.
Join the community:
Create a free account
Support DU (and get rid of ads!):
Become a Star Member
Latest Breaking News
General Discussion
The DU Lounge
All Forums
Issue Forums
Culture Forums
Alliance Forums
Region Forums
Support Forums
Help & Search
Scientists Identify 69 Drugs to Test Against the Coronavirus
NYT
March 22, 2020
Two dozen of the medicines are already under investigation. Also on the list: chloroquine, a drug used to treat malaria.
The researchers sought drugs that also latch onto the human proteins that the coronavirus seems to need to enter and replicate in human cells. The team eventually identified 24 drugs approved by the Food and Drug Administration to treat such seemingly unrelated diseases as cancer, Parkinson’s disease and hypertension.
On the list were such unexpected candidates as haloperidol, used to treat schizophrenia, and metformin, taken by people with Type 2 diabetes.
The investigators also found candidates among compounds that are now in clinical trials or that are the subject of early research. Intriguingly, some of the possible treatments are drugs used to attack parasites.
And the list includes antibiotics that kill bacteria by gumming up the cellular machinery they use to build proteins. But some of those drugs also attach to human proteins. The new study raises the possibility that this side effect might turn out to be an antiviral treatment.
One drug on the list, chloroquine, kills the single-celled parasite that causes malaria. Scientists have long known that it can also attach to a human cellular protein called the sigma-1 receptor. And that receptor is also the target of the virus.
On the list were such unexpected candidates as haloperidol, used to treat schizophrenia, and metformin, taken by people with Type 2 diabetes.
The investigators also found candidates among compounds that are now in clinical trials or that are the subject of early research. Intriguingly, some of the possible treatments are drugs used to attack parasites.
And the list includes antibiotics that kill bacteria by gumming up the cellular machinery they use to build proteins. But some of those drugs also attach to human proteins. The new study raises the possibility that this side effect might turn out to be an antiviral treatment.
One drug on the list, chloroquine, kills the single-celled parasite that causes malaria. Scientists have long known that it can also attach to a human cellular protein called the sigma-1 receptor. And that receptor is also the target of the virus.
https://www.nytimes.com/2020/03/22/science/coronavirus-drugs-chloroquine.html?action=click&module=Latest&pgtype=Homepage
Here's the real interesting part--the paper itself: https://www.biorxiv.org/content/10.1101/2020.03.22.002386v1.full.pdf
Discussion
We have used affinity purification-mass spectrometry to identify 332 high-confidence SARS-CoV-2-
human PPIs. We find the viral proteins connected to a wide array of biological processes, including protein
trafficking, translation, transcription and ubiquitination regulation. Using a combination of a systematic
chemoinformatic drug search with a pathway centric analysis, we uncovered close to 70 different drugs and
compounds, including FDA approved drugs, compounds in clinical trials as well as preclinical compounds,
targeting parts of the resulting network. We are currently testing these compounds for antiviral activity and
encourage others to do the same as well as extract insights from the map that could have therapeutic value.
More generally, this proteomic/chemoinformatic analysis is not only identifying drug and clinical
molecules that might perturb the viral-human interactome, it gives these potentially therapeutic perturbations a
mechanistic context. Among those that may be infection relevant are the inhibition of lysosomal acidification and
trafficking with Bafilomycin A1, via inhibition of V-ATPase71, and modulation of the ER stress and the protein
unfolding response pathway by targeting the Sigma1 and Sigma2 receptor by drugs like haloperidol (Fig. 5a,
Tables 1a,b). Indeed, several of the human proteins in the interactome are targeted by drugs that have emerged
phenotypically as candidate therapeutics for treating Covid-19, such as chloroquine72,73. While we do not pretend
to have identified the molecular basis of chloroquine’s putative activity, we do note that this drug targets the
Sigma1 and Sigma2 receptors at mid-nM and low mM concentrations, respectively. Similarly, antibiotics like
azithromycin have also been mooted as treatments for Covid-19. While this too remains to be demonstrated,
we note that Azithromycin has off-target activity against human mitochondrial ribosomes, components of which
interact with the SARS-CoV-2 Nsp8 protein (MRPS5, MRPS27, MRPS2, and MRPS25). Other antibiotics that
also have an off-target effect on mitochondrial ribosomes, such as chloramphenicol, tigecycline, and
Linezolid74,75 may also merit study for efficacy. Indeed, this logic may be extended. Many Covid-19 patients will
be on the drugs identified here, treating pre-existing conditions. It may be useful to correlate clinical outcomes
with the taking of these drugs, cross-referencing with the networks described here. In some senses, this is
already occurring phenomenologically, leading to concerns about ACE inhibitors such as captopril and enalapril,
and for NSAIDs. What this study provides is a systematic schema for making such clinical/drug associations
going forward, giving them a mechanistic context that allows investigators to seek them directly.
Systematic genetic validation using genetic-based approaches76,77 will be key to determine the functional
relevance of these interactions and if the human proteins are being used by the virus or are fighting off infection,
information that would inform future pharmacological studies. It is important to note that pharmacological
intervention with the agents we identified in this study could be either detrimental or beneficial for infection. For
instance, the HDAC2 inhibitors may compound the potential action of the Nsp5 protease to hydrolyze this human
protein. Future work will involve generation of protein-protein interaction maps in different human cell types, as
well as bat cells, and the study of related coronaviruses including SARS-CoV, MERS-CoV and the less virulent
OC435, data that will allow for valuable cross-species and viral evolution studies. Targeted biochemical and
structural studies will also be crucial for a deeper understanding of the viral-host complexes, which will inform
more targeted drug design.
Along with SARS-CoV-2, we have previously utilized global affinity purification-mass spectrometry (APMS) analysis to map the host-pathogen interfaces of a number of human pathogens including Ebola22, Dengue30,
Zika30, Herpesvirus29, Hepatitis C28, Tuberculosis27, Chlamydia26 , Enteroviruses25, HIV19, HPV24, and West Nile
Fever23. Excitingly, we have uncovered both shared and unique mechanisms in which these pathogens co-opt
author/funder. It is made available under a CC-BY 4.0 International license.
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.22.002386. The copyright holder for this preprint (which was not peer-reviewed) is the the host machinery during the course of infection. Although host-directed therapy is often not explored for combatting pathogenic infections, it would be interesting to use this information to identify host factors that could serve as targets that would harbor pan-pathogenic activity so that when the next virus undergoes zoonosis, we will have treatment options available.
We have used affinity purification-mass spectrometry to identify 332 high-confidence SARS-CoV-2-
human PPIs. We find the viral proteins connected to a wide array of biological processes, including protein
trafficking, translation, transcription and ubiquitination regulation. Using a combination of a systematic
chemoinformatic drug search with a pathway centric analysis, we uncovered close to 70 different drugs and
compounds, including FDA approved drugs, compounds in clinical trials as well as preclinical compounds,
targeting parts of the resulting network. We are currently testing these compounds for antiviral activity and
encourage others to do the same as well as extract insights from the map that could have therapeutic value.
More generally, this proteomic/chemoinformatic analysis is not only identifying drug and clinical
molecules that might perturb the viral-human interactome, it gives these potentially therapeutic perturbations a
mechanistic context. Among those that may be infection relevant are the inhibition of lysosomal acidification and
trafficking with Bafilomycin A1, via inhibition of V-ATPase71, and modulation of the ER stress and the protein
unfolding response pathway by targeting the Sigma1 and Sigma2 receptor by drugs like haloperidol (Fig. 5a,
Tables 1a,b). Indeed, several of the human proteins in the interactome are targeted by drugs that have emerged
phenotypically as candidate therapeutics for treating Covid-19, such as chloroquine72,73. While we do not pretend
to have identified the molecular basis of chloroquine’s putative activity, we do note that this drug targets the
Sigma1 and Sigma2 receptors at mid-nM and low mM concentrations, respectively. Similarly, antibiotics like
azithromycin have also been mooted as treatments for Covid-19. While this too remains to be demonstrated,
we note that Azithromycin has off-target activity against human mitochondrial ribosomes, components of which
interact with the SARS-CoV-2 Nsp8 protein (MRPS5, MRPS27, MRPS2, and MRPS25). Other antibiotics that
also have an off-target effect on mitochondrial ribosomes, such as chloramphenicol, tigecycline, and
Linezolid74,75 may also merit study for efficacy. Indeed, this logic may be extended. Many Covid-19 patients will
be on the drugs identified here, treating pre-existing conditions. It may be useful to correlate clinical outcomes
with the taking of these drugs, cross-referencing with the networks described here. In some senses, this is
already occurring phenomenologically, leading to concerns about ACE inhibitors such as captopril and enalapril,
and for NSAIDs. What this study provides is a systematic schema for making such clinical/drug associations
going forward, giving them a mechanistic context that allows investigators to seek them directly.
Systematic genetic validation using genetic-based approaches76,77 will be key to determine the functional
relevance of these interactions and if the human proteins are being used by the virus or are fighting off infection,
information that would inform future pharmacological studies. It is important to note that pharmacological
intervention with the agents we identified in this study could be either detrimental or beneficial for infection. For
instance, the HDAC2 inhibitors may compound the potential action of the Nsp5 protease to hydrolyze this human
protein. Future work will involve generation of protein-protein interaction maps in different human cell types, as
well as bat cells, and the study of related coronaviruses including SARS-CoV, MERS-CoV and the less virulent
OC435, data that will allow for valuable cross-species and viral evolution studies. Targeted biochemical and
structural studies will also be crucial for a deeper understanding of the viral-host complexes, which will inform
more targeted drug design.
Along with SARS-CoV-2, we have previously utilized global affinity purification-mass spectrometry (APMS) analysis to map the host-pathogen interfaces of a number of human pathogens including Ebola22, Dengue30,
Zika30, Herpesvirus29, Hepatitis C28, Tuberculosis27, Chlamydia26 , Enteroviruses25, HIV19, HPV24, and West Nile
Fever23. Excitingly, we have uncovered both shared and unique mechanisms in which these pathogens co-opt
author/funder. It is made available under a CC-BY 4.0 International license.
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.22.002386. The copyright holder for this preprint (which was not peer-reviewed) is the the host machinery during the course of infection. Although host-directed therapy is often not explored for combatting pathogenic infections, it would be interesting to use this information to identify host factors that could serve as targets that would harbor pan-pathogenic activity so that when the next virus undergoes zoonosis, we will have treatment options available.
The drug list begins on page 20. This is no doubt a technical paper, but some people with experience in this area might be able to glean which targets these scholars looking at for potential breakthroughs.
3 replies
= new reply since forum marked as read
= new reply since forum marked as read
