From the journal RSC Chemical Biology Peer review history

21-Dec-2020

Dear Dr Xu:

Manuscript ID: CB-REV-11-2020-000219
TITLE: Biological functions of supramolecular assemblies of small molecules in cellular environment

Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below.

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Yours sincerely,
Prof Seung Bum Park

Associate Editor, RSC Chemical Biology
Professor, Chemistry Department, Seoul National University, Korea

************

Reviewer 1

The manuscript reviews the recent progress of supramolecular assemblies of small molecules (SASMs) and the biological functions. This manuscript introduced the most recent literature related to the development and biological applications of SASMs, including anticancer and antimicrobial therapy, sustain physiological functions of cells and exploration of cell behavior. At last, the authors discussed the further opportunities of SASMs from both the mechanisms of self-assembly and the chemical nature of compositions. The designed SASMs present a novel direction supramolecular chemical biology.
Overall, the context within this manuscript is well in order. We recommend the acceptance of this manuscript in RSC Chemical Biology after a minor revision which should improve the resolution of certain figures (for example, Figure 8a and Figure 9). It is not easy to read the chemical structures and texts.

Reviewer 2

In this manuscript, Xu and co-workers summarized recent work of supramolecular assemblies of small molecules (SASMs) in cellular environment. They described several biological functions of SASMs that highlighted the importance of SASMs. I recommend acceptance of this manuscript with minor changes.
1) The 'Outlook' section would be more inspiring if the authors could list current challenges in this area and give perspectives about how to addressing current these challenges.
2) The length of scale bars were missing in many figures, e.g. Figure 10B and Figure 11C.

Reviewer 3

This review article well summarizes recent progress of supramolecular assemblies of small molecules (SASMs) in live cell context and its functions including inhibition of tumor growth, suppression of bacterial infection, promotion of cellular proliferation/differentiation, and others. The authors mainly focus on the enzyme-initiated supramolecular assembly of small (peptide) molecules and discuss the cutting-edge results and the scope. It is well described, which can appeal the readers of RSC chemical biology. Therefore, this is recommended for publication after minor correction.
1 Alkaline phosphatase (ALP) is frequently used for the trigger as summarized in this review. The location of ALP is rather confusing in the manuscript. In page 6, the authors describes “cytosolic overexpressed ALP”, while Figure 1B shows ALP seems to be membrane-bound and the sentence of page 8 shows overexpressed ALP on cancer cells. The authors should refer appropriate literatures on the location of ALP and properly explain it.
2 The last sentence of page 7 describes that SASMs can interact multiple targets and thus reduce side effects. This seems to be strange on the basis of conventional pharmaceuticals. The authors should explain it more carefully.

Reviewer 4

Wang and coauthors reviewed the recent progresses in the field of small molecular assembly in this article. Overall, this article is a very nice fit for the journal with emphasize on the chemical biology aspect of materials science. After minor revision, it will be ready for publication.

1. In the abstract, authors defined the term ‘supramolecular assemblies of small molecules (SASMs)’ and applied it as the essential subject for this review article. Later, authors used molecular self-assembly to describe the fundamental cellular process in biology. To distinguish the synthetic system from the biological system, distinct terms or clearer definitions are recommended.
2. There are massive publications in the field of small molecular assembly with biomedical applications. Since the authors only selected a few to be addressed in this review article, the specificity and important contribution of these selected ones in the field should be highlighted.
3. Some of the subtitles are too broad, while only few articles were properly mentioned under the topic. I recommend the authors tailor the subtitles for proper fit to their contents.
4. Some of the figures show unsatisfied image qualities. The authors are recommended to improve them. At least, the chemical structures should be clearly presented.

The following are our responses to the comments (in Italics) of the reviewer and the changes (underlined) in the manuscripts.

A) Referee 1
[The manuscript reviews the recent progress of supramolecular assemblies of small molecules (SASMs) and the biological functions. This manuscript introduced the most recent literature related to the development and biological applications of SASMs, including anticancer and antimicrobial therapy, sustain physiological functions of cells and exploration of cell behavior. At last, the authors discussed the further opportunities of SASMs from both the mechanisms of self-assembly and the chemical nature of compositions. The designed SASMs present a novel direction supramolecular chemical biology. Overall, the context within this manuscript is well in order.]
We are grateful for the comments of the reviewer. We agree with the reviewer that SASMs present a novel direction of supramolecular chemical biology.

[We recommend the acceptance of this manuscript in RSC Chemical Biology after a minor revision which should improve the resolution of certain figures (for example, Figure 8a and Figure 9). It is not easy to read the chemical structures and texts.]
We thank the reviewer for the comments. Following the suggestion of the reviewer, we have revised the Figure 3, Figure 4, Figure 7, Figure 8 and Figure 9.

B）Referee 2
[In this manuscript, Xu and co-workers summarized recent work of supramolecular assemblies of small molecules (SASMs) in cellular environment. They described several biological functions of SASMs that highlighted the importance of SASMs. I recommend acceptance of this manuscript with minor changes.]
We are grateful for the comments of the reviewer. We agree with the reviewer that this work highlighted the importance of SASMs.

[1) The 'Outlook' section would be more inspiring if the authors could list current challenges in this area and give perspectives about how to addressing current these challenges.]
We thank the reviewer for the suggestion. Following the suggestion of the reviewer, we expanded the Outlook section.

Addition:
Although SASMs show therapeutic effect on some diseases, many challenges still exist. For example, MDR in cancer and bacteria therapies still threatens human health. It is essential to increase the activities of SASMs to minimize the emergence of MDR. For instance, immunotherapy, a safe and efficient solution, is able to treat cancer with SASMs as the adjuvant.[118] Bacterial biofilm microenvironment might be a novel target to improve the efficacy of SASMs.[119] SASMs applying in tissue engineering and regenerative medicine is at the beginning, but there is a concern of amyloidogenicity of aggregates. This issue requires careful kinetic control of the formation of SASMs to avoid inducing amyloid formation of endogenous biomolecules. Moreover, enhancing the activation of multipotent proteins is efficient to promote the use of SASMs in tissue engineering and regenerative medicine, such as in bone regeneration.[120] It is likely that the further understanding of enzymatic noncovalent synthesis in biology[24] will also help address current challenges of SASMs in disease treatment.

[2) The length of scale bars were missing in many figures, e.g. Figure 10B and Figure 11C.]
We thank the reviewer for pointing out the missing of scale bars. We added labeled scale bars in Figure 10B and Figure 11C.

C）Referee 3
[This review article well summarizes recent progress of supramolecular assemblies of small molecules (SASMs) in live cell context and its functions including inhibition of tumor growth, suppression of bacterial infection, promotion of cellular proliferation/differentiation, and others. The authors mainly focus on the enzyme-initiated supramolecular assembly of small (peptide) molecules and discuss the cutting-edge results and the scope. It is well described, which can appeal the readers of RSC chemical biology. Therefore, this is recommended for publication after minor correction.]
We are grateful for the comments of the reviewer. We agree with the reviewer that this work can appeal the readers of RSC chemical biology.

[1 Alkaline phosphatase (ALP) is frequently used for the trigger as summarized in this review. The location of ALP is rather confusing in the manuscript. In page 6, the authors describes “cytosolic overexpressed ALP”, while Figure 1B shows ALP seems to be membrane-bound and the sentence of page 8 shows overexpressed ALP on cancer cells. The authors should refer appropriate literatures on the location of ALP and properly explain it.]
We thank the reviewer for the comments. To address the concern of the reviewer, we made a revision to minimize the confusion.

Original:
As shown in Figure 1B, compound 3, a phosphorylated peptide bearing peptide AVPI, an antagonist to the inhibitors of apoptotic proteins (IAPs) that impede the anticancer drug BTZ, is capable to incorporate BTZ and to enter cancer cells by endocytosis. Cytosolic overexpressed alkaline phosphatase (ALP) in these cells cuts off the hydrophilic phosphate groups, converting the micelles of “3” to the nanofibers of “4”, antagonizing IAPs and releasing BTZ to inhibit cancer cells.

Revision:
As shown in Figure 1B, compound 3, a phosphorylated peptide bearing peptide AVPI, an antagonist to the inhibitors of apoptotic proteins (IAPs) that impede the anticancer drug BTZ, is capable to incorporate BTZ. Normally, alkaline phosphatase (ALP), which exists both at intra- and extracellular space,[39] is overexpressed in/on cancer cells and acts as the cancer biomarker. The quantity of ALP is based on the type of the cancer cells. [39] Herein, the micelles of “3” interact with ALP from cells surface to initiate the endocytosis to enter cancer cells, cytosolic overexpressed ALP in these cells cuts off the hydrophilic phosphate groups, converting the micelles of “3” to the nanofibers of “4”, antagonizing IAPs and releasing BTZ to inhibit cancer cells.

[2 The last sentence of page 7 describes that SASMs can interact multiple targets and thus reduce side effects. This seems to be strange on the basis of conventional pharmaceuticals. The authors should explain it more carefully.]
To address the concern of the reviewer, we revised the sentence to clarify the mechanism for interacting with multiple targets.

Original:
Moreover, SASMs are also able to interact multiple targets or to disrupt multiple pathways in cancer cells,[42] which makes SASMs attractive molecular entities for killing cancer cells effectively, reducing side effects, and minimizing MDR in cancer therapy.[43,44]

Revision:
Moreover, SASMs, being generated by a specific enzymatic reaction, are also able to interact multiple targets or to disrupt multiple pathways in cancer cells,[43] which makes SASMs attractive molecular entities for killing cancer cells effectively, reducing side effects, and minimizing MDR in cancer therapy.[44,45]

D）Referee 4
[Wang and coauthors reviewed the recent progresses in the field of small molecular assembly in this article. Overall, this article is a very nice fit for the journal with emphasize on the chemical biology aspect of materials science. After minor revision, it will be ready for publication.]
We are grateful for the comments of the reviewer. We agree with the reviewer that this article fits the scope of the journal.

[1. In the abstract, authors defined the term ‘supramolecular assemblies of small molecules (SASMs)’ and applied it as the essential subject for this review article. Later, authors used molecular self-assembly to describe the fundamental cellular process in biology. To distinguish the synthetic system from the biological system, distinct terms or clearer definitions are recommended.]
We thank the reviewer for the comment. To address the concern of the reviewer, we made a definition in the revision.

Original:
In fact, the advances in several unrelated fields (e.g., biomaterials, drug screening, and neurodegenerative diseases) over the past decade have highlighted the biological importance of the SASMs.

Revision:
In fact, the advances in several unrelated fields (e.g., biomaterials, drug screening, and neurodegenerative diseases) over the past decade have highlighted the biological importance of supramolecular assemblies of small molecules (SASMs), which is also a form of molecular self-assembly.

[2. There are massive publications in the field of small molecular assembly with biomedical applications. Since the authors only selected a few to be addressed in this review article, the specificity and important contribution of these selected ones in the field should be highlighted.]
We thank the reviewer for the comment. Following the suggestion of the reviewer, we added a sentence to highlight the rationality of the choice.

Addition:
Although considerable works have been published on small molecular assembly with biological applications, such as the applications of liposomes in biomedicine, we choose to review small peptides other than lipids because the structural diversity of peptides offer (almost) unlimited opportunity for designing functions via engineering the molecules and the processes of assemblies, especially in the context of enzymatic reactions.

[3. Some of the subtitles are too broad, while only few articles were properly mentioned under the topic. I recommend the authors tailor the subtitles for proper fit to their contents.]
We agree with the reviewer about this comment. Following the suggestion of the reviewer, we revised some of the subtitles.

Original:
2.2.1 Enzymes as the trigger to inhibit microbials

Revision:
2.2.1 Enzymes as the trigger to inhibit bacteria

Original:
2.2.2 SASMs combine with other bioactive entities

Revision:
2.2.2 SASMs combine with antibiotics and proteins

Original:
4.2 SASMs for enhancing molecular imaging

Revision:
4.2 SASMs for imaging molecular self-assembly

[4. Some of the figures show unsatisfied image qualities. The authors are recommended to improve them. At least, the chemical structures should be clearly presented.]
We thank the reviewer for the comment. Following the suggestion of the reviewer, we revised the figures to present chemical structures more clearly in Figure 3, Figure 4, Figure 7 and Figure 9 (Please see the reply to Reviewer 1).

05-Jan-2021

Dear Dr Xu:

Manuscript ID: CB-REV-11-2020-000219.R1
TITLE: Biological functions of supramolecular assemblies of small molecules in cellular environment

Thank you for submitting your revised manuscript to RSC Chemical Biology. After considering the changes you have made, I am pleased to accept your manuscript for publication in its current form. I have copied any final comments from the reviewer(s) below.

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With best wishes,

Prof Seung Bum Park

Associate Editor, RSC Chemical Biology
Professor, Chemistry Department, Seoul National University, Korea

Reviewer 2

The authors have addressed the comments and I suggest the acceptance of the paper as is.

Reviewer 1

The authors have addressed all the comments accordingly. Thus, we recommend the acceptance of this manuscript without further change.