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New Paper (Therapeutics): A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing #60

Open adamlmaclean opened 4 years ago

adamlmaclean commented 4 years ago

Title: A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Please paste a link to the paper or a citation here:

Link: https://www.biorxiv.org/content/10.1101/2020.03.22.002386v2

What is the paper's DOI?

DOI: https://doi.org/10.1101/2020.03.22.002386

Is this paper primarily relevant to Background, Diagnostics, or Therapeutics? (OK if more than one)

Therapeutics

Please list some keywords (3-10) that help identify the relevance of this paper to COVID-19

Which areas of expertise are particularly relevant to the paper (put an x in the brackets [x])?

Suggested questions to answer about each paper:

Any comments or notes?

Twitter thread with other info: https://twitter.com/fraser_lab/status/1241929245812592641

rando2 commented 4 years ago

Thank you for suggesting and summarizing this paper @alavendelm !

I believe @raghuyennamalli is also interested in taking a look. Raghu, we have updated the template since Adam posted his original summary. Would you be able to answer these questions (and then click the boxes to check them when they're answered?) Please let me know if you have any questions!

Questions to answer about each paper:

Please provide 1-2 sentences introducing the study and its main findings

Study question(s) being investigated:

How many/what drugs/combinations are being considered?

What are the main hypotheses being tested?

Study population:

What is the model system (e.g., human study, animal model, cell line study)?

What is the sample size? If multiple groups are considered, give sample size for each group (including controls).

For human studies:

What countries/regions are considered?
What is the age range, gender, other relevant characteristics?
What is the setting of the study (random sample of school children, inpatient, outpatient, etc)?
What other specific inclusion-exclusion criteria are considered?

For example, do the investigators exclude patients with diagnosed neoplasms or patients over/under a certain age?

Treatment assignment:

How are treatments assigned?

For example, is it an interventional or an observational study?

Is the study randomized?

A study can be interventional but not randomized (e.g., a phase I or II clinical trial is interventional but often not randomized).

Provide other relevant details about the design.

This includes possible treatment stratification (e.g., within litters for animal studies, within hospitals for human studies), possible confounding variables (e.g., having a large age range of individuals), possible risks of bias and how they are addressed (e.g., is there masking in a clinical trial? how are individuals chosen in an observational study?).

Outcome Assessment:

Describe the outcome that is assessed and whether it is appropriate.

For example: Is the outcome assessed by a clinician or is it self-reported? Is the outcome based on viral load or a functional measurement (e.g., respiratory function, discharge from hospital)? What method is used to measure the outcome? How long after a treatment is the outcome measured?

Are outcome measurements complete?

For example, are there individuals lost to follow up?

Are outcome measurements subject to various kinds of bias?

For example, a lack of masking in randomized clinical trials.

Statistical Methods Assessment:

What methods are used for inference?

For example, logistic regression, nonparametric methods.

Are the methods appropriate for the study?

For example, are clustered data treated independently or are clusters adjusted for, such as different hospitals or litters?

Are adjustments made for possible confounders?

For example, adjustment for age, sex, or comorbidities.

Results Summary:

What is the estimated association?

For example, is it an estimated odds ratio, a median difference in detected cases, etc?

What measures of confidence or statistical significance are provided?

For example, confidence intervals, p-values, and/or Bayes factors.

Interpretation of results for study population:

Can we make a causal interpretation for the individuals in the study of drug -> outcome, such as "taking drug A improves likelihood of survival twofold over taking drug B."

For example, with a well-performed animal study or randomized trial it is often possible to infer causality. If is an observational study, does it match up with some of the Bradford Hill criteria? https://www.edwardtufte.com/tufte/hill https://en.wikipedia.org/wiki/Bradford_Hill_criteria

Are there identified side effects or interactions with other drugs?

For example, is the treatment known to cause liver damage or to not be prescribed for individuals with certain comorbities?

Are there specific subgroups with different findings?

For example, do individuals with a specific baseline seem to do particularly well? Be particularly cautious with respect to multiple testing here.

Extrapolation of conclusions to other groups of individuals not specifically included in the study:

If the study is an animal study, which animal and how relevant is that model?

Is the model system appropriate? Is there evidence from past use that it's highly-relevant to therapeutic design in this context?

If it is a human study, what characteristics of the study population may support/limit extrapolation?

Summary of reliability

1-2 sentences on concluding remarks, including summary of strengths, weaknesses, limitations.

Progress

Check off the components as they are completed. If the component is not applicable, check the box as well.

raghuyennamalli commented 4 years ago

Please provide 1-2 sentences introducing the study and its main findings

The study is innovative in terms of identifying host factors that are involved with SARS-CoV-2. The simple approach to identify using AP-MS and extrapolation to available drugs that have been reported for these host factors makes this study worthwhile.

Study question(s) being investigated:

What proteins in the host cell interact with viral proteins (structural and non-structural)?

How many/what drugs/combinations are being considered?

An interesting question for this study. The number of drugs considered is 63 (Table 1a and 1b). But the numbers in the text totals up to 69. The word considered here means that they have done a database search and prioritized from more than 10K molecules that are known to interact with the identified host factors. However, none of these drugs have been tested for Covid-19. In other words these drugs are re-purposed and have potential. But, could be detrimental as well.

What are the main hypotheses being tested?

There are multiple proteins in the host cell that possibly get upregulated during viral entry and there is a high possibility of these proteins interact with various components of the virus at the protein level. Using recombinant expression and affinity purification coupled with mass spec data, can these interactions be mapped and if so, can the molecular details of these interactions identified.

Also, are there already FDA approved, high affinity, commercially available drugs for the host factors? If so, this could fill the gap of re-purposed drugs.

Study population:

Not applicable

What is the model system (e.g., human study, animal model, cell line study)?

HEK293T cells for transfection

What is the sample size? If multiple groups are considered, give sample size for each group (including controls).

Not applicable

For human studies:

Not applicable

What countries/regions are considered?

Not applicable

What is the age range, gender, other relevant characteristics?

Not applicable

What is the setting of the study (random sample of school children, inpatient, outpatient, etc)?

Not applicable

What other specific inclusion-exclusion criteria are considered?

For example, do the investigators exclude patients with diagnosed neoplasms or patients over/under a certain age? Not applicable

Treatment assignment:

Not applicable

How are treatments assigned?

Not applicable

Is the study randomized?

Not applicable

Provide other relevant details about the design.

Not applicable

Outcome Assessment:

Not applicable

Describe the outcome that is assessed and whether it is appropriate.

The outcome is that there are drugs that can be repurposed for Covid-19 patients to alleviate the symptoms. However, they could be detrimental as well.

Are outcome measurements complete?

Not applicable

Are outcome measurements subject to various kinds of bias?

Not applicable

Statistical Methods Assessment:

What methods are used for inference?

Not applicable

Are the methods appropriate for the study?

Not applicable

Are adjustments made for possible confounders?

Not applicable

Results Summary:

What is the estimated association?

Not applicable

What measures of confidence or statistical significance are provided?

Not applicable

Interpretation of results for study population:

Can we make a causal interpretation for the individuals in the study of drug -> outcome, such as "taking drug A improves likelihood of survival twofold over taking drug B."

Not applicable

Are there identified side effects or interactions with other drugs?

Yes, that's the reason the authors have made the statement bold, where they say "It is important to note that pharmacological intervention with the agents we identified in this study could be either detrimental or beneficial for infection"

Are there specific subgroups with different findings?

Not applicable

Extrapolation of conclusions to other groups of individuals not specifically included in the study:

If the study is an animal study, which animal and how relevant is that model?

Not applicable

If it is a human study, what characteristics of the study population may support/limit extrapolation?

Not applicable

Summary of reliability

1-2 sentences on concluding remarks, including summary of strengths, weaknesses, limitations.

So the strength is the molecular level interaction of the host cell that have an affinity to bind with various viral components. This is very crucial to have a map of the druggablility of the virus. This has been done meticulously. The weakness is that we do not know the timeline as to which host factor interacts first (except for the literature on ACE2) and thus which could be a potential target to focus to prevent the virus at various stages. Do we want to prevent it from entry? Do we want to enter but not proliferate? Do we want to remain dormant even after entry and thus precent maturation? etc.. This is crucial information that can be tested to see with mature and immature virions and subsequent microscopy imaging. The limitation of the study is that the authors have listed the 63/69 drugs that need no further approval (except for few in pre-clinical/clinical stages), but the viral load reduction after drug in the HEK293T cells is not present. Thus, this list of drugs is at best a speculation that it will work to mitigate the symptoms of Covid-19.

Progress

Check off the components as they are completed. If the component is not applicable, check the box as well.

adamlmaclean commented 4 years ago

Thanks @raghuyennamalli great summary!