Review Reports

Round 1

Reviewer 1 Report

The HMOX1 pathway as a promising target for the 2treatment and prevention of SARS-CoV-2 of 2019 3(COVID-19)

Neelu Batra, Cristabelle De Souza, Jyoti Batra, Alan G. Raetz and Ai-Ming Yu1

The coronavirus disease of 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global pandemic with increasing incidence and mortality rates.

Authors descried the recent evidence based on the cytokine profiles of severe COVID-19 cases suggests an overstimulation of macrophages and monocytes associated with reduced T-cell abundance (lymphopenia) in patients infected with SARS-CoV-2.The SARS-CoV-2 Open Reading Frame 3 a (ORF3a) protein was found to bind to the human HMOX1 protein at a high confidence through high-throughput screening experiments. Authors described that the HMOX1 pathway can inhibit platelet aggregation, and have anti-thrombotic and anti-inflammatory properties amongst others, all of which are critical medical conditions observed in COVID-19 patients. Manuscript indicated the potential of modulating the HMOX1-ORF3a nexus can regulate the innate immune response for therapeutic benefits in COVID-19 patients. Authors also review other potential treatment strategies and suggest novel synthetic and natural compounds that may have the potential for future development in hospitalised patients such as Remdesivir, Hydroxychloroquine and chloroquine, Azithromycine, convalescent plasma and antibody-based therapies, actemra, kaletra (lopinasvir/ritonavir), tamiflu (oseltamivir), and avigan (favipiravir).

Due to the subject of the work related to the most important pathogen that the whole world has encountered, this type of research is crucial and necessary to fully understand the biology of the virus and to fight this pathogen.

I consider the work valuable and I propose that this work be published in the International Journal of Molecular Sciences

Author Response

Comment #1: Authors descried the recent evidence based on the cytokine profiles of severe COVID-19 cases suggests an overstimulation of macrophages and monocytes associated with reduced T-cell abundance (lymphopenia) in patients infected with SARS-CoV-2.The SARS-CoV-2 Open Reading Frame 3 a (ORF3a) protein was found to bind to the human HMOX1 protein at a high confidence through high-throughput screening experiments. Authors described that the HMOX1 pathway can inhibit platelet aggregation, and have anti-thrombotic and anti-inflammatory properties amongst others, all of which are critical medical conditions observed in COVID-19 patients. Manuscript indicated the potential of modulating the HMOX1-ORF3a nexus can regulate the innate immune response for therapeutic benefits in COVID-19 patients. Authors also review other potential treatment strategies and suggest novel synthetic and natural compounds that may have the potential for future development in hospitalised patients such as Remdesivir, Hydroxychloroquine and chloroquine, Azithromycine, convalescent plasma and antibody-based therapies, actemra, kaletra (lopinasvir/ritonavir), tamiflu (oseltamivir), and avigan (favipiravir).

Due to the subject of the work related to the most important pathogen that the whole world has encountered, this type of research is crucial and necessary to fully understand the biology of the virus and to fight this pathogen.

I consider the work valuable and I propose that this work be published in the International Journal of Molecular Sciences. 

[Response] The authors truly appreciate the reviewer for her/his pertinent and positive comments and recommendation.

Reviewer 2 Report

-In line 231 where it says "SARS--CoV2" should be "SARS-CoV-2"

-In line 260-261 while numbering the activities, the anti-inflammatory one is listed twice.

-In line 259 says "natural compounds that could show promise for therapy" but in the following line (260) it talks about plants and not about compounds ("One such natural plant is the Neem plant"). Overall, it seems that sometimes there is some mix between the concepts of "natural compounds" and "plants"/"extracts" (extracts, or plants, include several types of compounds, not just one). Also, around line 285 (ref 109) it is mentioned the evaluation of an ethanolic extract (that could contain artefacts due to the nucleophilic action of ethanol), and when evaluating extracts it is difficult to attribute the activity to a molecule (in extracts there are many molecules that could create synergies, and also the presence and the amount of the existing molecules depend on several factors during the harvest, such as temperature, season, date, etc)

-In lines 305-306 where it says "of natural compounds like neem" should say "of plants like neem" as it seems to be referring to the plant.

-When talking about Nimbolide (line 263) and Azadirachtin (line 270) it should be interesting to talk about what type of compounds they are, and/or put the structure of the molecules.

Author Response

Comment #1: In line 231 where it says "SARS--CoV2" should be "SARS-CoV-2".

[Response] Thank you. It is corrected in the revised manuscript.

Comment #2: In line 260-261 while numbering the activities, the anti-inflammatory one is listed twice.

[Response] It is corrected.

Comment #3: In line 259 says "natural compounds that could show promise for therapy" but in the following line (260) it talks about plants and not about compounds ("One such natural plant is the Neem plant"). Overall, it seems that sometimes there is some mix between the concepts of "natural compounds" and "plants"/"extracts" (extracts, or plants, include several types of compounds, not just one). Also, around line 285 (ref 109) it is mentioned the evaluation of an ethanolic extract (that could contain artefacts due to the nucleophilic action of ethanol), and when evaluating extracts it is difficult to attribute the activity to a molecule (in extracts there are many molecules that could create synergies, and also the presence and the amount of the existing molecules depend on several factors during the harvest, such as temperature, season, date, etc).

[Response] Thank you. The authors are referring to compounds/extracts obtained from naturally occurring plants like the neem plant. This correction has now been added to line 259.

Line 285 mentions that we are referring to the ethanolic ‘extract’ of neem and not the molecule. While we agree with the reviewer that results from studies looking at the potency of neem extracts need to be interpreted with caution, we do believe that preliminary studies performed on natural extracts would serve as a good starting point before delving into more time and cost consuming studies aimed at identification and discovery of the potent molecule within the whole extract.

Comment #4: In lines 305-306 where it says "of natural compounds like neem" should say "of plants like neem" as it seems to be referring to the plant.

[Response] The authors agree with the reviewer. Change has been made on lines 305-306.

Comment #5: When talking about Nimbolide (line 263) and Azadirachtin (line 270) it should be interesting to talk about what type of compounds they are, and/or put the structure of the molecules.

[Response] Thank you very much. We have now added short descriptions of the chemical entities Nimbolide and Azadirachtin on their respective lines. Additionally, we have provided a PubChem ID next to Nimbolide and Azadirachtin so readers can avail of the detailed chemical characteristics of each molecule.