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greenelab / covid19-review

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New Paper (Therapeutic): Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion #280

Open matfax opened 4 years ago

matfax commented 4 years ago

Title: Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

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

Link: https://www.nature.com/articles/s41422-020-0305-x

What is the paper's Manubot-style citation?

Citation: doi:10.1038/s41422-020-0305-x

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?

matfax commented 4 years ago

Questions to answer about each paper:

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

In this paper, Shuai Xia et al. improved their previous in-house pan-coronavirus inhibitor EK1 to target the SARS-CoV-2 S protein. Their new optimized inhibitor EK1C4 showed significantly enhanced effectiveness against the SARS virus group in vitro and against HCoV-OC43 in vivo.

Study question(s) being investigated:

How many/what drugs/combinations are being considered?

Initially, they evaluated many different EK1 derivatives. Extended validation was done only on EK1 and EK1C4.

What are the main hypotheses being tested?

  1. Due to new mutations in SARS-CoV-2 in the HR2 domain, they hypothesize that EK1 could be further improved.
  2. Based on their protein simulation, they found various new EK1 derivatives as potential candidates for an in vitro inhibition model. The hypothesis is that these new candidates show improved interaction when compared to EK1.
  3. Since EK1C4 showed the best improvement in vitro when compared to EK1, they hypothesize that it could also inhibit SARS-CoV-2 and other coronaviruses in vivo in an enhanced manner.

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

This study design is similar but smaller than their previous EK1 study (#276).

  1. The fluorescence model measured S protein-mediated cell-cell fusion from transfected 293 T effector cells to 293T/ACE2 (for SARS-CoV-2 S protein) or Huh-7 target cells (for all other S proteins) in the absence or presence of the EK1 candidates and the original EK1 in original and scrambled versions as control.
  2. Pseudoviruses encoding the respective S proteins and a defective luciferase-expressing HIV-1 genome from various viruses were created. Then, the viral concentration was measured by a luciferase assay on different target cell lines (i.e., 293T/ACE2 for the SARS virus group, RD cells for HCoV-OC43, Huh-7 for others) in the absence or presence of EK1C4, EK1, and a scrambled EK1 as control.
  3. The inhibitory effect on wild-type virus replication of SARS-CoV-2 and MERS-CoV was verified by a plaque reduction assay in the absence or presence of EK1C4, EK1, and a scrambled EK1 as control. Other viruses were measured by CPE in cell-counting assays (i.e., HCoV-OC43 in RD, HCoV-229E in Huh-7, and HCoV-NL63 in LLC-MK2).
  4. A mouse model was used to verify the prophylactic and therapeutic effect of EK1C4 on HCoV-OC43 infection.
  5. The cytotoxicity of EK1C4 was measured after a two-day incubation of Vero E6, Huh-7, LLC-MK2, and RD cells by cell counting.

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

Treatment assignment:

How are treatments assigned?

The administration was consistent.

Is the study randomized?

The selection process was randomized.

Provide other relevant details about the design.

The authors used a wide secondary vector (i.e., untreated, EK1C4-treated 0.5, 2, 4, 12, 24 hours pre-infection, and EK1C4-treated 0.5, 2 hours post-infection). Moreover, they used 0.5, 1, and 2 hour EK1-treatment pre-infection groups. Of each of the 12 mice in these groups, they used 1 for a histopathological check after 5 days, 5 for virus titer collection from the brain after 5 days, and the remaining 6 for body weight and survivability observation for 14 days. These details had to be derived from the methods section, the results section, and supplementary documentation because it is not accurately described in the methods section per se.

Outcome Assessment:

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

The survivability was measured for 14 days. Viral load was tested after 5 days.

Are outcome measurements complete?

Within the EK1C4 group, they are complete.

Are outcome measurements subject to various kinds of bias?

There is no obvious bias.

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."

No conclusions can be made for SARS-CoV-2. EK1C4 might improve the survivability from human coronaviruses in general when given as prophylactic or early after infection.

Are there identified side effects or interactions with other drugs?

EK1 didn't show histopathological damage in mice in their previous study. EK1C4 was only verified in mouse brain tissues and on different cell lines to be safe. Drug interactions haven't been verified.

Are there specific subgroups with different findings?

EK1C4 treatment 2 hours after infection did not show to improve survivability significantly. Only the 30-minute post-treatment group completely survived 14 days.

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?

The authors do not mention which mouse line they used. They used Balb/c in their previous study for HCoV-OC43 experiments.

Summary of reliability

The description of their methods seems to be incomplete and inaccurate in certain parts (e.g., the mouse model, and live virus cell lines). The enhanced potential of EK1C4 is clear when comparing its IC50. It is ca. two orders of magnitudes lower than the IC50 of EK1. Nonetheless, it seems to fall in the same group of virostatics that need to be taken as early as possible. That makes it impractical for a disease with such long incubation times as SARS-CoV-2. The EK1C4 peptide clearly targets the S protein but no controls were used to countercheck co-interactions with other proteins of SARS-CoV-2.

Progress

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

matfax commented 4 years ago

Feedback regarding the following questions would be particularly welcome: