Antiviral and Anti-Inflammatory Plant-Derived Bioactive Compounds and Their Potential Use in the Treatment of COVID-19-Related Pathologies

Round 1

Reviewer 1 Report

The manuscript “Anti-viral and anti-inflammatory roles of plant-derived bioactive compounds in managing COVID-19: a mechanism-based review” described well, the pathophysiology of COVID-19 as well as some plant-based bioactive compounds that may serve to cure/protect against COVID-19 co-morbidities. The following points seemed to be worth including:

1.  However, the inclusion of structures of the compounds mentioned would make the manuscript more informative, relatable to the information provided and enhance its widespread acceptance by readers.

2.     Also, the inclusion of a statistical analysis of the group of plant-derived compounds which are found to be effective against COVID19 and associated symptoms based on the literature survey would give a brief idea to the readers about which class of compounds to refer preferably for further study.

3.     Although, the authors have explained various mechanism-based treatment strategies for COVID19 treatment. Highlighting the factors of vaccine development and its underlying mechanisms would be appreciable.

4.     Inclusion of a section stating the in-silico aspects of the proteins and receptors involved as well as any up-to-date information regarding the in-silico binding of the stated plant derived compounds in the paper viz., polyohenols,  alkaloids, etc with those receptors, would add practicality to the paper.

5. A separate section for the marketed antivirals as well as plant based drugs/compounds that have shown good activity towards COVID19 or are in the clinical trial phase should be included that would increase the clarity in approach of the paper.

6. There is a bit lack of clarity in the concluding remark of the paper. A lot of existing literature based upon plant based compounds that may help to mitigate COVID19 has already been reported and also about existing drugs and compounds that have the possibility of repurposing for COVID19 treatment.

So, it is recommended to rewrite the conclusion and add a paragraph clearly stating the future perspectives and the take-home message by the readers.

 

Author Response

The manuscript “Anti-viral and anti-inflammatory roles of plant-derived bioactive compounds in managing COVID-19: a mechanism-based review” described well, the pathophysiology of COVID-19 as well as some plant-based bioactive compounds that may serve to cure/protect against COVID-19 co-morbidities. The following points seemed to be worth including:

1. However, the inclusion of structures of the compounds mentioned would make the manuscript more informative, relatable to the information provided and enhance its widespread acceptance by readers.

Response: Thank you very much for your suggestions! We have now included structures of the compounds in the revised review article (Figure 5).

 

2. Also, the inclusion of a statistical analysis of the group of plant-derived compounds which are found to be effective against COVID19 and associated symptoms based on the literature survey would give a brief idea to the readers about which class of compounds to refer preferably for further study.

 

Response: We appreciate the reviewer for the idea of including a statistical analysis of the group of plant-derived compounds effective against COVID-19. In the current review, we have focused on preclinical studies to assess the effects of bioactive compounds against COVID-19 since clinical studies are still ongoing and final results are not available yet. Therefore, a statistical analysis of different studies of bioactive compounds is not possible at this time.

 

 

3. Although, the authors have explained various mechanism-based treatment strategies for COVID19 treatment. Highlighting the factors of vaccine development and its underlying mechanisms would be appreciable.

 

Response: We appreciate the reviewer for the suggestion! However, it would be out of scope of this manuscript to describe the factors of vaccine development and its underlying mechanisms.

 

 

4. Inclusion of a section stating the in-silico aspects of the proteins and receptors involved as well as any up-to-date information regarding the in-silico binding of the stated plant derived compounds in the paper viz., polyohenols,  alkaloids, etc with those receptors, would add practicality to the paper.

 

Response: We thank the reviewer for the suggestion! We have already mentioned in-silico computational models in our article. Based on the suggestion, we have now added more in-silico molecular dynamic studies to demonstrate the effect of bioactive compounds on viral proteins or receptors to prevent COVID-19 viral replication and infection:

 

“Additionally, a molecular dynamic simulation study suggests a strong interaction of resveratrol to the S spike protein-ACE2 complex and likely inhibiting SARS-CoV-2 viral replication [57].

 

Furthermore, receptor binding and entry assay of 56 polyphenols in human alveolar epithelial cell line A549 revealed that curcumin has the highest binding affinity to the viral RBD of SARS-CoV-2 spike protein [59]. Molecular docking and molecular dynamic simulation studies also indicated that emodin blocks the interaction between SARS-CoV-2 S protein and ACE2 receptors [60]. 

 

Furthermore, in silico reports demonstrated suitable binding affinity of lycorine to 3CLpro of coronaviruses, especially the SARS-CoV-2.”

 

 

5. A separate section for the marketed antivirals as well as plant based drugs/compounds that have shown good activity towards COVID19 or are in the clinical trial phase should be included that would increase the clarity in approach of the paper.

 

Response: All anti-virals marketed at present are not plant-based compounds and therefore not part of this review. Instead of a separate section, we have included ongoing clinical trials in the substance-specific sections, e.g.:

 

“Importantly, there is an ongoing clinical trial of CBD to assess the efficacy and safety of CBD (300 mg/day) in patients infected with SARS-CoV-2. The objective of this study is the examine whether CBD administration in patients, decreases viral load, modify inflammatory response, reduce clinical and emotional symptoms and reduce hospitalization and the severity of the disease (NCT04467918).”

 

 

6. There is a bit lack of clarity in the concluding remark of the paper. A lot of existing literature based upon plant based compounds that may help to mitigate COVID19 has already been reported and also about existing drugs and compounds that have the possibility of repurposing for COVID19 treatment.

So, it is recommended to rewrite the conclusion and add a paragraph clearly stating the future perspectives and the take-home message by the readers.

 

Response: Based on the suggestion, we have now revised the conclusion of the review article as follows:

 

“In this review, mechanisms of SARS-CoV-2 infection including adhesion, entry and replication into host cells have been outlined to design potential treatment options. The anti-viral and anti-inflammatory effectiveness of plant-derived bioactive compounds has been previously decribed in HIV, HSP, influenza and MERS. With the ongoing COVID-19 pandemic, plant-derived bioactive compounds have gained attention for their possible use in mitigating SARS-CoV-2 infection. The majority of existing studies have tested the efficacy of these compounds using in silico computational models or in vitro cell culture models. However, there is still a lack of in vivo studies to demonstrate the effects of plant-derived bioactive compounds against COVID-19 infection. Several clinical studies are ongoing to assess the pharmacological potential of these compounds for managing symptoms associated with COVID-19 infection. Furthermore, clinical studies demonstrating the relationship between dietary aspects of plant-derived compounds and prevention of complications of COVID-19 infections will provide a valuable information in recommending bioactive compounds as nutritional supplements and their applications as nutraceuticals against SARS-CoV-2 infection.”     

Author Response File: Author Response.pdf

Reviewer 2 Report

This is an interesting paper summarazing knowledge on potential application of natural compounds in mitigation of SARS-Cov-2 infection - thus it is a review paper. Paper is well written, well organized and accompanied by suitable Figures. Paper is divided into two parts - first one discussing the physiology of Covid-19 - both viral infection physiology and non-beneficial immuno-response, and the second showing the possible interactions of  natural compounds with both. The current knowledge about Covid-19 and natural compounds is not very extensive, however, is well collected by Authors and definitely is worth reviewing. Summing up, paper is suitable for publication in present form.

Author Response

This is an interesting paper summarizing knowledge on potential application of natural compounds in mitigation of SARS-Cov-2 infection - thus it is a review paper. Paper is well written, well organized and accompanied by suitable Figures. Paper is divided into two parts - first one discussing the physiology of Covid-19 - both viral infection physiology and non-beneficial immuno-response, and the second showing the possible interactions of natural compounds with both. The current knowledge about Covid-19 and natural compounds is not very extensive, however, is well collected by Authors and definitely is worth reviewing. Summing up, paper is suitable for publication in present form.

 

Response: We would like to thank the reviewer for the encouraging comments!

 

 

Author Response File: Author Response.pdf

Reviewer 3 Report

At first glance this manuscript seems to have its meaning, but it takes considerable academic evidence to support the publication of a review paper. This manuscript only has a good starting point, but I think the contribution to the reader is limited. Because of the references mentioned in this manuscript are mostly cell experiments, few animal experiments, no have human experiments. This is why so far, apart from antibodies, few drugs with real efficacy have been developed. Not to mention some of the plant compounds in the manuscript. I'm not saying that these plant compounds are not helpful, in terms of fighting viruses, especially COVID-19, it may only be a relief for some of its symptoms, but there is a long way to go before it becomes a recognized drug long distance. Therefore, it may be more appropriate to try not to involve COVID-19 for this title, because the composition of Chinese herbal medicines is complex, and its mechanism of action on the human body is indescribable. We believe that it may be intentional for the body but we do not understand its true mechanism of action and its dose, this is a very dangerous thing for patients. Although the topic of COVID-19 is very hot and popular now, as a scholar, you should face things with conscience. Although there is a lot of evidence from cell experiments for both disease maps and anti-inflammation in the references, what I want to emphasize is which compound or combination has been tested in humans and confirmed to be effective? If not, it does not make much sense. .

Author Response

At first glance this manuscript seems to have its meaning, but it takes considerable academic evidence to support the publication of a review paper. This manuscript only has a good starting point, but I think the contribution to the reader is limited. Because of the references mentioned in this manuscript are mostly cell experiments, few animal experiments, no have human experiments. This is why so far, apart from antibodies, few drugs with real efficacy have been developed. Not to mention some of the plant compounds in the manuscript. I'm not saying that these plant compounds are not helpful, in terms of fighting viruses, especially COVID-19, it may only be a relief for some of its symptoms, but there is a long way to go before it becomes a recognized drug long distance. Therefore, it may be more appropriate to try not to involve COVID-19 for this title, because the composition of Chinese herbal medicines is complex, and its mechanism of action on the human body is indescribable. We believe that it may be intentional for the body but we do not understand its true mechanism of action and its dose, this is a very dangerous thing for patients. Although the topic of COVID-19 is very hot and popular now, as a scholar, you should face things with conscience. Although there is a lot of evidence from cell experiments for both disease maps and anti-inflammation in the references, what I want to emphasize is which compound or combination has been tested in humans and confirmed to be effective? If not, it does not make much sense. .

 

Response: We would like to thank the reviewer for the comments highlighting some very important issues. As outlined in response to reviewer #1 (e.g., comments #2 and #5), several clinical studies are ongoing, and it is indeed too early to know whether there will be an efffective plant-derived medication for COVID-19. However, based on our literature review – as mentioned by the reviewer – there is a lot of preclinical evidence for potential anti-viral and anti-inflammatory efficacy of plant-derived bioactive compounds. We are very conscious about the present limitations in evidence and revised our summary and conclusion section accordingly.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors have improved the manuscript significantly satisfying most the queries . I feel that the manuscript could accepted for publication.

Author Response

We would like to thank the reviewer for the valuable feedback to help us improve the manuscript

Reviewer 3 Report

I still think the title of this manuscript and the content are not so appropriate. It seems to make readers misunderstood, and it is suggested that the title should be revised.

Author Response

We would like to thank the reviewer again for the thoughtful comment. According to the reviewer's suggestion we changed the title from:

"Anti-viral and anti-inflammatory roles of plant-derived bioactive compounds in managing COVID-19: a mechanism-based review" to:

"Anti-viral and anti-inflammatory plant-derived bioactive compounds for their potential use in the treatment of COVID-19-related pathologies"