https://orcid.org/0000-0001-9964-281X
Peer Review History
| Original SubmissionJune 1, 2020 |
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Transfer Alert
This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.
Dear Prof. Barrett, Thank you very much for submitting your manuscript "Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication. Prior to acceptance please address the points raised by the reviewers. They are of a minor nature and no additional experimentation should be required. Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out [2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments. Sincerely, Dominique Soldati-Farve Associate Editor PLOS Pathogens Margaret Phillips Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** Reviewer Comments (if any, and for reference): Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: Benzoxyboroles are promising compounds to develop as drugs for treatment of trypanosome infections in animals. The rise of resistance to this type of compound is concerning. The authors present compelling evidence that resistance is due to loss of serine carboxypeptidase activity in the parasite. This implies the test compound is a prodrug. Reviewer #2: The manuscript by Paape et al reports on the discovery that highly potent trypanocidal benzoxaborole compounds are prodrugs that are activated by serine carboxypeptidases in the trypansome cells. This is an important and significant study because it elucidates the mechanism of strong potency (and mechanism of resistance) of this particular compound class, as well as illustrating a general mechanism (prodrug processing) in trypanosomes that has relevance to other arenas of drug discovery. Through numerous experimental approaches, the investigators rigorously and convincingly demonstrate that the serine carboxypeptidases are responsible for the prodrug processing and that mutations in the genes are responsible for drug resistance. The paper is written clearly and logically. Reviewer #3: The benzoxaboroles are an important class of trypanocides. Two molecules, SCYX-7158 (acoziborole) and AN11736, are in clinical development for human African trypanosomiasis and nagana, respectively. Paape et al. have selected T. congolense and T. brucei for resistance to AN11736. The obtained mutants were cross-resistant to other benzoxaboroles with a peptide-bond linker, and, based on whole genome sequencing, the mutants appeared to have lost paralogues of the serine carboxypeptidase (CBP) gene cluster on chromosome 10. The nature of the deletion was not further investigated, nor were expression levels of the CBP genes. Nevertheless, the authors convincingly demonstrate by reverse genetics that AN11736 is a prodrug that is cleaved by trypanosomal CBP after uptake, and that this mechanism sensitizes the trypanosomes to AN11736, presumably by creating a sink effect. I find this a conclusive and important piece of work and recommend it for publication in PLoS Pathogens. ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: The key experiments and observations include identifying a compound fragment in wild type treated parasites that by MS conforms to a carboxypeptidase-generated fragment. Reviewer #2: The data are thorough and adequately support their conclusions. No additional experiments are recommended. Reviewer #3: none ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: none Reviewer #2: The Discussion did not include any mention of the natural function of the serine carboxypeptidases in these trypanosomes. It is interesting that the parasites with mutations in these genes had normal growth and ability to infect mice. Do the authors think these proteases may play a role in the procyclic life-cycle stage? Also, the final sentence of the Discussion may need further explanation. How would it help to have a different linker design with targeted activity by the trypanosome carboxypeptidases? It would probably still be subject to resistance by mutations of the peptidases in the parasites. Reviewer #3: 1. line 116: "had increased" 2. line 128: the trypanosomes were resistant, not the compounds 3. line 428: what was the DMSO concentration? 4. figure 1, right panel: "% Survival" is not clear. Was this really a survival assay or should it read "% Growth"? ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Frederick S Buckner Reviewer #3: No Figure Files: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Data Requirements: Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5. 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| Revision 1 |
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Dear Prof. Barrett, We are pleased to inform you that your manuscript 'Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Dominique Soldati-Favre Associate Editor PLOS Pathogens Margaret Phillips Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************************************************** Reviewer Comments (if any, and for reference): |
| Formally Accepted |
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Dear Prof. Barrett, We are delighted to inform you that your manuscript, "Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs," has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens |
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