Plasmodial Transcription Factors and Chromatin Modifiers as Drug Targets

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review article, titled "Plasmodial Transcription Factors and Chromatin Modifiers as Potential Drug Targets," underscores the vital role of transcription factors in the development of the parasite. Surprisingly, only a limited number of studies have explored these proteins as targets for drug development. While the article is generally well-written, I am deeply concerned about the numerous typographical and grammatical errors that need correction before publication. I strongly recommend that the authors conduct a thorough review of the article to ensure that no errors remain. For more detailed comments, please consult the attached PDF.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Minor editing of the English language is required.

Author Response

reviewer 1:

The review article, titled "Plasmodial Transcription Factors and Chromatin Modifiers as Potential Drug Targets," underscores the vital role of transcription factors in the development of the parasite. Surprisingly, only a limited number of studies have explored these proteins as targets for drug development. While the article is generally well-written, I am deeply concerned about the numerous typographical and grammatical errors that need correction before publication. I strongly recommend that the authors conduct a thorough review of the article to ensure that no errors remain. For more detailed comments, please consult the attached PDF.

Dear Reviewer 1,

Thank you very much for Your critical reading and input. We have addressed all the points you highlighted in the pdf, and I comment on critical ones in the following. The other formal mistakes (spaces, italics, etc.) were corrected throughout.

The highlighted item in line 72 was reformulated.

We have also reformulated the complicated sentence in line 137ff.

 

 

pdf is attached

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Plasmodial Transcription factors and Chromatin modifiers as drug targets

In this review, the authors examine transcription factors and chromatin modifiers of Plasmodium falciparum as potential therapeutic targets against this parasite, taking advantage of their specificity, and in some cases their absence in Human and mosquitoes.

The overall quality of the work is commendable, and it provides a review of the existing literature, focusing on three categories of transcription factors and chromatin modifiers: Histone acetylases and histone deacetylases, histone methyltransferases and histone demethylases, and ApiAP2 Transcription Factors, with implications for malaria control.

I have some comments that should be considered:

·         In the abstract the author’s state:

“and proposes future strategies to effectively combat the parasite by disturbing its control of gene expression.”

I think it is too ambitious and does not agree with the conclusions; although they review the topic, they are not really proposing strategies, they propose possible targets for further studies and raise some problems about the strategies that are currently used.

·         There are a few language-related issues in the manuscript that require attention.

o   They must clarify that there are two types of tests to which they refer, in vitro when referring to P. falciparum and in an animal model with other parasites when referring to a murine model, in these revisions please clarify that the term "murine model" refers to experiments conducted with mice as an animal model and eliminates any ambiguity in the language used:

L13-14

“In recent years, several unique transcription factors and chromatin modifiers have been identified in Plasmodium falciparum, and in animal models, including murine species.”

This phrase is not clear, the work does not talk about the identification of these factors in murine species.

L298-299

“The knockout of AP2-L in a murine model, which involves genetically altering mice, does not affect the invasion of merozoites into hepatocytes.”

Clarify the knock out is done to mice? What does the murine model refer to?

L327-328

“It is important to highlight that in the case of both P. falciparum and murine models, the SIP2…”

Clarify murine model.

L25 The phrase "with P. falciparum carrying the highest mortality risk" is somewhat vague, and it doesn't specify what the mortality risk is being compared to.

L121 “while the toxicity of C14 fibroblast was at least 40 times lower”

The toxicity of C14 in fibroblast?

L170-171 The statement "values that are tenfold more potent against P. falciparum compared to normal human cell types" can be confusing, since it refers to tests that talk about IC50 values on the HDAC enzymes of the parasite or human, not of the cells, when talking about normal cells one could think of uninfected versus infected cells.

L329  In the phrase “Despite being smaller than the average size of others”

What others are they referring to?

 

·         They should clarify the nomenclature and at least mention the database when they mention the different genes. (PF3D7_0730300, PF3D7_0604100, PF3D7_0622900)

 

·         Please review the presentation of the references within the text, there are some that are found in individual square parentheses, there are also missing spaces between the text and the reference.

 

·         Some reason for just the subtitle…. Histone Methyltransferases and Histone Demethylases Is this underlined?

 

·         Please review and define abbreviations:

L357 NCC

L 359 SCC

L364 GV

·         Some italics are missing in Latin expressions such as 'in vivo,' 'et al.,'

Author Response

reviewer 2:

Plasmodial Transcription factors and Chromatin modifiers as drug targets

In this review, the authors examine transcription factors and chromatin modifiers of Plasmodium falciparum as potential therapeutic targets against this parasite, taking advantage of their specificity, and in some cases their absence in Human and mosquitoes.

The overall quality of the work is commendable, and it provides a review of the existing literature, focusing on three categories of transcription factors and chromatin modifiers: Histone acetylases and histone deacetylases, histone methyltransferases and histone demethylases, and ApiAP2 Transcription Factors, with implications for malaria control.

I have some comments that should be considered:

·         In the abstract the author’s state:

“and proposes future strategies to effectively combat the parasite by disturbing its control of gene expression.”

I think it is too ambitious and does not agree with the conclusions; although they review the topic, they are not really proposing strategies, they propose possible targets for further studies and raise some problems about the strategies that are currently used.

We have changed the final phrase of the abstract.

There are a few language-related issues in the manuscript that require attention.
They must clarify that there are two types of tests to which they refer, in vitro when referring to P. falciparum and in an animal model with other parasites when referring to a murine model, in these revisions please clarify that the term "murine model" refers to experiments conducted with mice as an animal model and eliminates any ambiguity in the language used:

L13-14

“In recent years, several unique transcription factors and chromatin modifiers have been identified in Plasmodium falciparum, and in animal models, including murine species.”

This phrase is not clear, the work does not talk about the identification of these factors in murine species.

We modified the phrase to address this ambiguity: “In recent years, several unique transcription factors and chromatin modifiers have been identified and partially characterized in Plasmodium falciparum and in the murine species P. yoelii and P. berghei.”

L298-299

“The knockout of AP2-L in a murine model, which involves genetically altering mice, does not affect the invasion of merozoites into hepatocytes.”

Clarify the knock out is done to mice? What does the murine model refer to?

We apologize for the severe mistake in the text. We now corrected the phrase as follows: “The knockout of AP2-L in the P. berghei model of infection does not affect the invasion of sporozoites into hepatocytes;…”

L327-328

“It is important to highlight that in the case of both P. falciparum and murine models, the SIP2…”

Clarify murine model.

We have changed the sentence as follows: “It is important to highlight that in the case of both P. falciparum and the murine species P. berghei, the SIP2…”

L25 The phrase "with P. falciparum carrying the highest mortality risk" is somewhat vague, and it doesn't specify what the mortality risk is being compared to.

We have edited the sentence to: “…poses a significant public health threat, with P. falciparum being the main species that causes deaths.”

L121 “while the toxicity of C14 fibroblast was at least 40 times lower”

The toxicity of C14 in fibroblast?

We have corrected the phrase as follows:  “…while the toxicity of C14 in human fibroblasts was at least 40 times lower “

L170-171 The statement "values that are tenfold more potent against P. falciparum compared to normal human cell types" can be confusing, since it refers to tests that talk about IC50 values on the HDAC enzymes of the parasite or human, not of the cells, when talking about normal cells one could think of uninfected versus infected cells.

We apologize for the misleading expression here and changed this sentence: “These compounds inhibited P. falciparum at IC50 values up to tenfold lower compared with their inhibitory action against human cell lines [49].”

L329 In the phrase “Despite being smaller than the average size of others”

What others are they referring to?

We have changed the sentence to: “Despite this AP2 domain showing a smaller size than the average of other AP2 domains in P. falciparum, this domain enables PfAP2-Tel to directly …”

 

·         They should clarify the nomenclature and at least mention the database when they mention the different genes. (PF3D7_0730300, PF3D7_0604100, PF3D7_0622900)

We now mention that the informed gene IDs of the pattern Pf3D7…are from the www.plasmoDB.org database (indicated in new line 271).

 

·         Please review the presentation of the references within the text, there are some that are found in individual square parentheses, there are also missing spaces between the text and the reference.

We have gone through the text and corrected this issue.

 

·         Some reason for just the subtitle…. Histone Methyltransferases and Histone Demethylases Is this underlined?

 

·         Please review and define abbreviations:

L357 NCC

L 359 SCC

L364 GV

·         Some italics are missing in Latin expressions such as 'in vivo,' 'et al.,'

We have deleted the abbreviations NCC and SCC as they appear only once. GDV1 is now explained. We have carefully gone to the text and put the relevant expressions in italic.

 

Author Response File: Author Response.pdf