Synthesis of a Cyclooctapeptide, Cyclopurpuracin, and Evaluation of Its Antimicrobial Activity
, Dadan Sumiarsa 1,2, Kindi Farabi 1,2,3, Tri Mayanti 1,2, Nurlelasari 1,2, Desi Harneti 1,2 and Unang Supratman 1,2,3
Round 1
Reviewer 1 Report
The manuscript entitled “Synthesis of a cyclooctapeptide, cyclopurpuracin, and evaluation of its antimicrobial activity” reported the synthesis of two cyclopurpuracin-derived cyclic peptides through the combination of solid- and solution-phase synthesis. Their antimicrobial activity was evaluated against S. aureus, E. coli, and C. albicans using a microdilution test.
Finally, I have to raise the following minor issues.
- Introduction (Lines 37-41): In the literature, there are many cyclic antimicrobial peptides obtained through the application of several kind of cyclizations, including both head-to-tail and side chain-to-side chain cyclizations. The authors should describe these different approaches and add some references such as “Pharmaceutics. 2022 Feb 21;14(2):454. doi: 10.3390/pharmaceutics14020454”; Mar Drugs. 2022 Jun; 20(6): 397. doi: 10.3390/md20060397. These papers can support cyclization strategies as an approach to enhance antimicrobial activity.
- Line 88: The authors state that glycine is the b-turn inductor similar to Proline but I think it is not completely correct. In fact, in the peptide chemistry, glycine is usually used as a spacer and it is a flexible amino acid. Please, should modify this sentence.
- Introduction (Lines 77–120): The introduction usually describe the state of art of a work, while the authors describe in detail the obtained results. It is better to describe the state of the art on cyclopurpuracin and move these many information in the results section.
- Results: The authors just reported the NMR results but it is not satisfying. The authors should improve this section by adding the peptide synthesis and Table 1 that they reported in the discussion. The authors should add the antimicrobial activity and the table with the MICs values in the results.
- Discussion: Maybe, the authors should include the Results and discussion in one section because the format of the paper is a bit complicated to understand for the readers. Please, improve this aspect.
Author Response
Dear Reviewer,
Thank you for the comments for our manuscript. Herewith, I attached our response to the comments.
Thank you.
Regards,
Rani
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This research article by Rani Maharani and coworkers reported the synthesis of cyclooctapeptide and cyclopurpuracin by a combination of solid- and solution-phase synthetic methods from linear cyclopurpuracin. The cyclization product’s structure has been confirmed by HRMS and NMR. Importantly, the author conducted a microdilution test and the results showed that the cyclization products have weak activity with MIC values of 1000 µg/mL. The manuscript is well organized and written. I think the manuscript deserves to be published in Molecules after minor revision.
1) Line 60: “Figure 2.” Should be “Figure 2.” (?), there is no Figure 1.
2) From 140 lines: “DMSO-d6” should be “DMSO-d6”, same correction to 151-156 lines.
3) Line 175: Please indicate the ratio of “AcOH:TFE:DCM”.
4) Line 407, there is extra space.
5) Line 421: “H2O” Should be “H2O”.
6) In the reference part, all of the references using full journal name, suggest using abbreviation.
Author Response
Dear Reviewer,
Thank you for the comments for our manuscript. Herewith, I attached our response to the comments.
Thank you.
Regards,
Rani
Author Response File: Author Response.pdf
Reviewer 3 Report
This research is focused on the first total synthesis of cyclopurpuracin (cyclo-Gly-Phe-Ile-Gly-Ser-Pro-Val-Pro) through a combination of solid and solution-phase method. The topic is significantly original owing to the first synthesis of cyclopurpuracin A & B. Moreover, the synthesized compounds have been characterized by 1H-NMR, 13C-NMR spectroscopy and mass spectrometry. The authors have also described the specific gap.
Overall, the formatting and description of methodology is well-reported. Authors have provided description about 1H-NMR and 13C-NMR spectroscopy. But relevant 1H-NMR and 13C-NMR spectras of cyclopurpuracin synthesized from precursor A & B need to be provided in supplementary information. Moreover, 13C-NMR spectrum of precursor B is missing in supplementary data.
· Line 60, its not ‘’Figure 2’’. Correct the numbering.
· In scheme 1, structures and arrows should be equally spaced throughout the manuscript. It is better to keep some space between structure and each arrow to give a clean outlook.
· Line 262, it should be Table 2. Recheck and update.
· Line 307, it should be referred as ‘’Table 3’’.
· Line 325, It should be labelled as ‘’Table 4’’.
Other Remarks:
1- Line 14, ‘’of cyclopurpuracin’’ should be omitted.
2- Line 15, add space between ‘’eventhough’’
3- Line 17 & 61, remove dash after solid.
4- Line 17, add word ‘’by’’ before word ‘’using’’.
5- Line 23, add and before ‘’13C-NMR’’
6- Line 22, word ‘’products’’ should be replaced with ‘’product’’.
7- Line 42, add comma after ‘’ gramicidin S’’
8- Line 23, remove comma before word ‘’respectively’’.
9- Line 47, add the word ‘’the’’ after ‘’one of’’.
10- Line 70, add ‘’the’’ after word ‘’following’’
11- Line 74 & 75 needs to be re-written.
12- Line 77, add ‘’the’’ before ‘’cyclization’
13- Line 69, modify the sentence.
14- Sentence between the ‘’83-85’’ lines need to be re-written.
15- Line 173, remove extra spacing.
16- Line 157, remove extra spacing.
17- Two consecutive paragraphs after scheme 1 are almost similar. Differentiate them.
18- Line 104, result should be replaced with ‘’results’’.
19- Line 110, add ‘’the’’ before’’cyclization of’’
20- Line 146, there should be table 2.
21- Line 230, add space before and after the equality sign.
22- Line 234, replace word ‘’condition’’ with ‘’conditions’’.
23- Line 245, add comma after ‘’flexibility’’.
24- Line 258, remove dash after C.
25- Line 266, remove extra space.
26- Line 268 & 269 need to be re-written.
27- Line 283, add ‘’and’’ before C-NMR.
28- Line 407, remove extra space.
29- Line 402, add space between number and degree.
30- Re-write the sentence in line 379 & 380.
31- Line 372, remove extra space.
English language needs to be carefully checked and improved.
Author Response
Dear Reviewer,
Thank you for the comments for our manuscript. Herewith, I attached our response to the comments.
Thank you.
Regards,
Rani
Author Response File: Author Response.pdf
Round 2
Reviewer 3 Report
The authors have revised the manuscript and it can now be accepted in current form.
