Therapeutic Targets in the Virological Mechanism and in the Hyperinflammatory Response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2)

Round 1

Reviewer 1 Report

This article provides a comprehensive review about the therapeutic targets in the virological mechanism and in the  hyperinflammatory response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV2). Overall, the article is well-written. I just have one minor suggestion.

Part of section 7 and 9 need to be updated after incoporating clinical studies and discuss about their effect about the SARS-CoV-2 variants.

In the section 7 (Therapy in the viral response phase) and section 9 (Therapy in the hyperinflammatory response phase with immunomodulators of the immune inflammatory cascade), many clinical studies had assessed the efficacy of these anti-viral agents. The authors should add more discussion after adding the findings of the associated clinical studies. In addition, please add the recommendation of the current guidelines. Finally, the authors need to cautiously interpret their findings because some of the mentioned agents were not recommended for treating COVID-19.

Based on the above rationales, I will recommend “accept after minor revision”

Author Response

Dear reviewer,
We appreciate the review as well as your input. In relation to the comments, we proceed to respond:
1) Part of sections 7 and 9 should be updated after incorporating clinical studies and analyzing their effect on SARS-CoV-2 variants. In section 7 (Therapy in the viral response phase) and section 9 (Therapy in the hyperinflammatory response phase with immunomodulators of the immunoinflammatory cascade), many clinical studies had evaluated the efficacy of these antiviral agents. Authors should add further discussion after adding findings from associated trials: we have reviewed the rationale and consider the information complete and adequate. If the reviewer considers that we should add some specific information, we are willing to incorporate it.
2) The translation has been reviewed by the language department of the University.
We remain at your disposal for any question you deem appropriate.

Reviewer 2 Report

Authors have nicely reviewed therapeutic targets in the virological mechanism and in the hyperinflammatory response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV2).

1. The similarity index is 31%. Which is higher. Authors are suggested to check it again.

2. Some of the abbreviations are such as "protein S", HADDOCK,  are not described.

3. In some of the reference DOI is missing.

Author Response

Dear reviewer,
We appreciate the review as well as your input. In relation to the comments, we proceed to respond:
1) The similarity index is 31%. What is higher Authors are suggested to review it again: the article is original, even so, it has been completely revised.
2) Some of the abbreviations such as "S protein" are not described, HADDOCK: it is the spike protein (line 181). It has been detailed and specified. Haddock is not an abbreviation.
3) Some of the references are missing DOI: it has been reviewed. Some references do not have a DOI.
4) The translation has been reviewed by the language department of the University.
We remain at your disposal for any questions you deem appropriate.

Reviewer 3 Report

Comments for author File: Comments.pdf

Author Response

Dear reviewer,
We appreciate the review as well as your input. In relation to the comments, we proceed to respond:
1) Lines 28, repeat sentence (severe acute respiratory syndrome 28 coronavirus 1): corrected.
2) The Authors described the main features of the HCov structure. Since the manuscript refers to SARS-CoV2, could the authors specify the peculiarity of this virus with respect to the other members of the HCoV?
interaction between HCov and host cells: this is a theoretical argument to detail the functions of the virus.
3) In section two, it might be useful to briefly describe the infection mechanism: we have reviewed this consideration. We have considered that the basic explanation is sufficient.
4) The authors were able to clearly describe the methods: a literature review was performed on the criteria of a systematic review.
5) The methods section could be moved earlier in the text. (for example, section 3 will become section 2 and section 2 will become section 3). This advice is because the later sections of Methods refer to the structural and biochemical characteristics of coronaviruses: corrected and modified.
6) Lines106- -CoV1 encodes three proteins: 3a, E and 8a. The 3a and E proteins contain a PDZ-binding motif (PBM), which can bind to more than 400 cellular proteins 107 that contain a PDZ domain [34,35]. W Why do the authors emphasize the fact that SARS cov1 encodes three E proteins, if the work focuses on sarscov2? Is it relevant?: We appreciate the consideration. In the argument we only give the detail, we do not go into the explanation of content, we consider that it is important.
7) Line 109 4. Biochemistry- The acronym hcov was previously defined. Please remove it from the title: fixed.
8) Why do the authors refer to the mechanisms of HCoV infection and not specifically to SARS-CoV2?: This argument responds to both a consideration that it explained and this one. It is necessary for the information of the reader.
9) How do the Authors want to correlate sections 1-4 with the 5th? Suddenly they start with COVID 19, without any kind of introduction about it: the subtitles 1 to 4 themselves give the argument of COVID19.
10) Lines 148. Insert a reference relative to the therapeutic approach: corrected.
11) Please briefly describe the three phases of figure 2 in the main text, also introducing the cytokine response: corrected and incorporated in the heading paragraph 5.
12) Section 6. Please, introduce and correlate the edema in pulmonary alveoli and then explain and describe the therapeutic objectives: we have synthesized the information so that it can be understood in the best possible way.
13) Before describing therapies, it is necessary to describe the covid 19 disease, the symptoms, the molecular response and the cytokine storm, main characteristics: points 1 to 6.
14) The translation has been reviewed by the language department of the University.
We remain at your disposal for any questions you deem appropriate.

Round 2

Reviewer 3 Report

Dear Authors, maybe you missed sime points that I asked you. Moreover, I'm not able to visualize the modifications apported after the 1st review round. could you please hilight these?

Comments for author File: Comments.pdf

Author Response

Dear reviewer,
We appreciate your assessment and your contributions. Regarding the points that you have indicated:
1) Are the authors sure of the accuracy of the term “hyperinflammatory cascades” in lines 17? In fact, the term "hyperinflammation" refers to an inflammatory response that is too high, but the molecular pathway is inflammation: yes, we have reviewed that connotation of the paper, and the facultative investigator confirms that it is correct.
2) Line 112 "Union of the spike...". Not a “join”, despite an interaction!!: Modified in text.
3) How do the Authors want to correlate sections 1-4 with the 5th? Suddenly they start with COVID 19, without any kind of introduction about it: in sections 1 to 4 a physiological and pathophysiological analysis is carried out to elaborate the fundamental pillar of the main explanation of COVID19.
4) Lines 143 “a response phase against SARS-CoV2”. Could the authors further clarify this sentence? What is the meaning of “response against SARS-CoV2”? What is the relationship with the etiopathogenesis?: the paragraph has been modified.
5) Lines 148. Insert a reference relative to the therapeutic approach: added.
6) Please briefly describe the three phases of Figure 2 in the main text, also introducing the cytokine response: it is marked in the text.
7) Before describing therapies, there is a need to describe the covid 19 disease, the symptoms, the molecular response and the cytokine storm, main characteristics of the disease...... and then the therapies: see answer 3.
8) Line 262 "Two major phases have been differentiated:...". Two main phases of what? Patient response to infection?: modified and marked in the manuscript.
Thank you very much for your assessment and contributions.
Kind regards,

Round 3

Reviewer 3 Report

The manuscript is now suitable for the publication