From the journal RSC Chemical Biology Peer review history

Berlin, 3 October 2023

Dear Dr Spring:

Manuscript ID: CB-ART-09-2023-000176
TITLE: Visible-light modulated <i>ortho</i>-chloro azobenzene photoswitch for peptide stapling via aromatic substitution

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Yours sincerely,
Prof. Dr. Roderich Süssmuth
Technische Universität Berlin
Faculty II - Mathematics and Natural Sciences
RSC Chemical Biology Associate Editor

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Reviewer 1

This will be a useful addition to the journal.
I can see that it narrowly missed out on Chem Sci and that the reviewers' comments were addressed.
A few comments:
Avoid repetition:
"stapled peptide SP1 for MDM2, a competitive fluorescence polarisation (FP) assay was carried out"........
"were determined using a competitive fluorescence polarisation assay with the FP tracer peptide. "


"the linear peptide P1 was found to have a reduced binding affinity, as expected upon the introduction of two cysteine residues"
-please elaborate. Because it is linear or because of the 2 Cys? Why?

The final statement about incomplete cis/trans conversion and a comparison with R/S-ibuprofen needs to be elaborated/caveated; 1. you don't have a final drug, this would need many cycles of development/assays/trials to reach market. 2. There are many instances of toxicity with mixtures of enantiomers, cf. thalidomide.

Re: Response to reviewer comments of “Visible-light modulated ortho-chloro azobenzene photoswitch for peptide stapling via aromatic substitution”

Dear Prof. Roderich Süssmuth,

Thank you very much to you and the reviewer for the feedback on the manuscript. The feedback is much appreciated, and we firmly believe it improved the manuscript.

Please find our point-to-point response below.

Reviewer #1
Avoid repetition:
"stapled peptide SP1 for MDM2, a competitive fluorescence polarisation (FP) assay was carried out"........
"were determined using a competitive fluorescence polarisation assay with the FP tracer peptide. "
We want to thank the reviewer for the suggestion, we have emended the sentence structure in the revised manuscript to avoid repetition.

“the linear peptide P1 was found to have a reduced binding affinity, as expected upon the introduction of two cysteine residues"
-please elaborate. Because it is linear or because of the 2 Cys? Why?
The results observed were elaborated in more detail in the revised version of the manuscript. The reduced binding affinity is attributed to a change in helical content which was observed for P1, compared to that of PMI which was previously reported and cited in the revised manuscript.

The final statement about incomplete cis/trans conversion and a comparison with R/S-ibuprofen needs to be elaborated/caveated; 1. you don't have a final drug, this would need many cycles of development/assays/trials to reach market. 2. There are many instances of toxicity with mixtures of enantiomers, cf. thalidomide.
We have deleted this statement in the revised manuscript because we only intended to highlight that the difference between the two different isomers may not be a major concern, but we agree that the example might not be the most representative for what we wanted to show.

Lastly, the title has been modified from "visible" to "red" light following Chem Sci reviewer suggestions.

Yours sincerely,

David Spring

Berlin, 5 October 2023

Dear Dr Spring:

Manuscript ID: CB-ART-09-2023-000176.R1
TITLE: Red-light modulated <i>ortho</i>-chloro azobenzene photoswitch for peptide stapling via aromatic substitution

Thank you for submitting your revised manuscript to RSC Chemical Biology. 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. Dr. Roderich Süssmuth
Technische Universität Berlin
Faculty II - Mathematics and Natural Sciences
RSC Chemical Biology Associate Editor

Reviewer 1

Perfect responses, all good, please accept.

John Spencer