Cyclic Peptides as Protein Kinase Modulators and Their Involvement in the Treatment of Diverse Human Diseases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In manuscript kinasesphosphatases-3344210, Martínez-Alcantar et al discuss cyclic peptides as protein kinase modulators and their involvement in the treatment of diverse human diseases. The topic of this manuscript is interesting and fits well the scope of the journal. The reviewer has no objection to pass this review article.

(1)   The abbreviation should be properly defined before use. In abstract, CDPs was used without proper definition.

(2)   “4 Discussion” is a bit odd. This is a review but not original research. Please avoid discussion. At the end of a review article, “Fure Perspective” is more appropriate. Please discuss of CDPs.

(3)   Please discuss the safety and drug-likeness of CDPS.

Author Response

Reviewer 1

Comments: In manuscript kinasesphosphatases-3344210, Martínez-Alcantar et al discuss cyclic peptides as protein kinase modulators and their involvement in the treatment of diverse human diseases. The topic of this manuscript is interesting and fits well the scope of the journal. The reviewer has no objection to pass this review article.

(1)   The abbreviation should be properly defined before use. In abstract, CDPs was used without proper definition.

(2)   “4 Discussion” is a bit odd. This is a review but not original research. Please avoid discussion. At the end of a review article, “Future Perspective” is more appropriate. Please discuss of CDPs.

(3)   Please discuss the safety and drug-likeness of CDPS.

Response to Reviewer 1:

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the revisions/corrections highlighted/in track changes in the re-submitted files.

Response 1: The abbreviations were defined at first use in the abstract; also, they were revised in all the text again.

Response 2: The reviewer has the right to decide that the discussion section is inappropriate for a review. As suggested, we modified the title to “Future perspectives” and extended the topic to include the therapeutic implications of CDPs.

Response 3: We added some ideas about the pharmacological security of some CDPs. The literature provides poor information.

Some information incorporated is: “ Regarding safety, initial studies indicate that CDPs have a low toxic profile in preclinical systems, particularly in cell cytotoxicity tests (185-187). This makes them attractive candidates for new drug development. However, challenges still relate to the specificity of their biological activity, stability in physiological media, and possible accumulation in tissues, which could influence their long-term safety. Therefore, more extensive studies, including in vivo assays and comprehensive toxicological analyses, are needed to ensure their safe use in humans. “....

Reviewer 2 Report

Comments and Suggestions for Authors

Lorena Martínez-Alcantar et al. submitted a paper entitled „Cyclic Peptides as Protein Kinase Modulators and their Involvement in the Treatment of diverse human diseases”. This is a review, with 212 citations, that focuses on new insights into the molecular mechanisms associated with the cytotoxicity of the CDPs (cyclodipeptides?), the target selectivity, and the possibility of designing more efficient drugs as protein kinase modulators. It should be mentioned that protein kinases are an important and very popular family of enzymes at play a vital role in regulating cellular processes via the phosphorylation of targets. Nevertheless, modifications in expression due to mutations or their dysregulation can lead to diseases, including autoimmune disorders, cardiovascular problems, diabetes, neurological diseases, and cancers. Cyclic ultra-short peptides are amazing structures with unique properties. The cyclicity of CDPs can mimic the interactions between protein kinase and natural substrates, influencing enzyme activity essential in health and disease physiology. The authors summarized that interference in the signal transduction mechanism of the protein kinase by CDPs implies the inhibition of the substrate phosphorylation at the level of the active site, similar to the antineoplastic drugs. The remarkable capacity of CDPs to interact with targets positions them as promising candidates for developing protein kinase inhibitors in treating diseases. Generally, the paper is worth publishing, because it can stimulate to further development of more effective and safe therapeutic agents. Cyclic dipeptides are still underrated. However, minor corrections are needed before acceptance. Ultra-short peptides are the main players in this work; hence they should be presented in a precise way. The authors should emphasize the advantages and disadvantages of ultra-short peptides in a better way – they can read and cite paper 10.3390/molecules26020430, presenting a SWOT analysis of these specific molecules and aspects of cyclicity. The authors did not explain what does it mean CDPs! The figures are original, prepared by authors? If not, they should have suitable approvals/agreements, etc. Figure 2 is rather a scheme, not a figure. In addition, it is of poor quality. The paper contains a lot of abbreviations. Maybe the authors should include a legend of abbreviations? Finally, the authors should carefully check and correct the text according to the Guide for authors.

Author Response

Reviewer 2

Comments and Suggestions for Authors

Lorena Martínez-Alcantar et al. submitted a paper entitled „Cyclic Peptides as Protein Kinase Modulators and their Involvement in the Treatment of diverse human diseases”. This is a review, with 212 citations, that focuses on new insights into the molecular mechanisms associated with the cytotoxicity of the CDPs (cyclodipeptides?), the target selectivity, and the possibility of designing more efficient drugs as protein kinase modulators. It should be mentioned that protein kinases are an important and very popular family of enzymes at play a vital role in regulating cellular processes via the phosphorylation of targets. Nevertheless, modifications in expression due to mutations or their dysregulation can lead to diseases, including autoimmune disorders, cardiovascular problems, diabetes, neurological diseases, and cancers. Cyclic ultra-short peptides are amazing structures with unique properties. The cyclicity of CDPs can mimic the interactions between protein kinase and natural substrates, influencing enzyme activity essential in health and disease physiology. The authors summarized that interference in the signal transduction mechanism of the protein kinase by CDPs implies the inhibition of the substrate phosphorylation at the level of the active site, similar to the antineoplastic drugs. The remarkable capacity of CDPs to interact with targets positions them as promising candidates for developing protein kinase inhibitors in treating diseases. Generally, the paper is worth publishing, because it can stimulate to further development of more effective and safe therapeutic agents. Cyclic dipeptides are still underrated. However, minor corrections are needed before acceptance. Ultra-short peptides are the main players in this work; hence they should be presented in a precise way. The authors should emphasize the advantages and disadvantages of ultra-short peptides in a better way – they can read and cite paper 10.3390/molecules26020430, presenting a SWOT analysis of these specific molecules and aspects of cyclicity. The authors did not explain what does it mean CDPs! The figures are original, prepared by authors? If not, they should have suitable approvals/agreements, etc. Figure 2 is rather a scheme, not a figure. In addition, it is of poor quality. The paper contains a lot of abbreviations. Maybe the authors should include a legend of abbreviations? Finally, the authors should carefully check and correct the text according to the Guide for authors.

General response:

Thank you very much for taking the time to review this manuscript. We have considered the modifications suggested in the abstract, which improved and helped focus the context discussed in the review.

 

For the reviewer questions, we answer as follows:

1.- The authors should emphasize the advantages and disadvantages of ultra-short peptides in a better way – they can read and cite paper 10.3390/molecules26020430, presenting a SWOT analysis of these specific molecules and aspects of cyclicity.

Response 1: We thank the reviewer for the commendation. Additional information was added in the paragraph (2.- Cyclic peptides as small molecule therapies through human protein kinase inhibitors), incorporating the findings related to ultra-short peptides cited in reference 10.3390/molecules26020430).

“Compared to small molecules used in conventional treatments, peptides exhibit several advantages, including reduced tissue accumulation, high selectivity, exceptional potency, and specific biotarget interaction. In this sense, ultra-short peptides, defined as sequences of up to 7 amino acids typically containing no more than 45 amino acids, stand out for their unique structural and functional properties. Ultra-short peptides present strengths and limitations; their immense potential as versatile scaffolds for diagnostics and therapeutic applications is undeniable (102). A key strategy for enhancing the performance of these peptides is cyclization, which stabilizes their active conformation. Cyclic ultra-short peptides not only retain the advantages of their linear counterparts, as it is, exhibiting enhanced mechanical stability, efficient tissue penetration, and reduced immunogenicity, along with bio- and cytocompatibility, characterized by non-hemolytic and non-cytotoxic behavior (103). Also, the cyclic ultra-short peptides in vivo improve stability, resistance to protease, and plasma degradation (103), high bioavailability (102), excellent membrane permeability (114), strong binding affinity (111), and limited conformational flexibility (104). These attributes make cyclic ultra-short peptides exceptionally versatile and position them as up-and-coming candidates for advancing therapeutic and diagnostic innovations.”

 

2.- The authors did not explain what does it mean CDPs!

Response 2: We thank the reviewer for the observation; we defined and clarified the definition of the abbreviation with more details in the text, and an additional figure was incorporated to show the CDPs context and structures (Figure 3).

 

3.- The figures are original, prepared by authors?

Response 3: Yes, we prepared the figures; some were adapted from papers published by our group, whose figures have been correctly cited.

 

4.- Figure 2 is rather a scheme, not a figure. In addition, it is of poor quality.

Response 4: The reviewer has the right; the type was changed to the scheme, performed again, and improved quality.

 

5.- The paper contains a lot of abbreviations. Maybe the authors should include a legend of abbreviations?

Response 5: The reviewer has the right; a list of abbreviations was performed as recommended and added as supplementary material.

6.- Finally, the authors should carefully check and correct the text according to the Guide for authors.

Response 6: We thank the reviewer for the recommendation and revised it according to the Guide for authors.