From the journal RSC Chemical Biology Peer review history

14-Oct-2021

Dear Professor Chen:

Manuscript ID: CB-ART-07-2021-000154
TITLE: Cyclic peptide drugs approved in last two decades (2001-2021)

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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I look forward to receiving your revised manuscript.

Yours sincerely,
Prof Seung Bum Park

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

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Reviewer 1

Zhang and Chen wrote a very important review of Cyclic peptide drugs approved in last two decades (2001-2021). Few other reviews of this kind exist of the literature, but based on the title, this one aims to be comprehensive. I like the idea of this review and I appreciate the importance of such review. However, I think it needs to be reformatted to convey two main messages:
1. This is a comprehensive review, there are no approved drugs that escaped this review: from 60 peptide drugs approved in the history of humanity N have been approved in the period from 2001-2021. From these N compounds, M (M<N) are macrocycles, and all M are discussed in this review.
2. Macrocycles are chemical compounds with atom-scale precision in composition (not just some formulated biological entities with poor composition).
3. Approved and withdrawn -- are there examples like that. What lesson did we learn?

As a result, I suggest two major editorial changes

1. Drugs (compounds) discussed in this review should be numbered 1,2,3,4... all the way to M (whatever M is). This way the reader knows what the number M is and they can also ensure that every compound has been discussed or at least mentioned.

2. There should be chem draw structure for every compound.

3. If something was approved and withdrawn -- the reader should know about it.

4. Money is important. Any mention of money in relation to approved drugs is alway a good reminder to scientist that this business works because someone is willing to pay for it. It doesn't have to be comprehensive but the scientific reader needs to be reminded that certain drugs that didn't make any money eventually "failed after approval" and this is the sad reality of drug business.

Reviewer 2

This review article highlights cyclic peptide drugs approved for clinical use during the last two decades. While it is a useful summary of such approved drugs, numerous similar reviews have been published in recent years. As it stands, this manuscript adds little information or context to the area of cyclic peptide drugs and significant additions and changes are required before it is suitable for publication.
1) The authors have restricted the review to clinically approved drugs, but many of the advances and modern methods they outline in the introduction and then detail in the main body and the conclusions are only applicable to peptides under investigation in clinical or pre-clinical trials, and have not yet been realized in terms of approved drugs. Further, in the introduction the authors state the review is restricted to cyclic peptides between 5-20 residues. It is not clear why this limit has been applied, given insulin is mentioned as the first cyclic peptide drug, yet is comprised of >50 residues.
2) The structure of the manuscript is confusing, with the peptides of interest divided into sections by their target; intracellular, extracellular, or microbial. But the authors also try to classify the compounds by their mode of production; natural products, semi-synthetic compounds or synthetic.
3) The authors state “peptide-based molecules with molecular weights >1000 Da are generally too large to be computationally calculated” but this is irrelevant as none of the approved drugs were designed through computational analysis.
4) The description of the biological activity of somatastatin at the top of column 2, page 5, should be incorporated earlier in the section on pasireotide.
5) The section on melanocortin receptor agonists should be re-structured as it is not clear for which indication bremelanotide is approved. Further, discussion of terlipressin in this section creates more confusion as it is not a melanocortin receptor agonist.
6) The section on antimicrobial agents is satisfactory, but none of these drugs have been approved more recently than 2014, so there is no new information.
7) The ‘Perspectives and conclusions’ sections introduces a lot of new information that is not relevant to the previous sections. For example, the passage “Directed evolutions with genetically displayed cyclic peptide recombinant libraries is increasingly playing more important roles in next-generation cyclic peptide drug discoveries. Display systems such as mRNA display, DNA display and phage display offer the advantages of large library diversity and rapid screening, and have resulted in the discovery of a good portion of cyclic peptides in clinic development” may be true, but is not directly relevant to the approved drugs covered in this review. If the authors wish to include such modern technologies in this review, they should expand the scope of the review to peptides in clinical and pre-clinical development. Such an expansion of scope would be a major undertaking, but without it this manuscript is essentially covering material already well reviewed in the literature.

Dear Professor Park,

Thank you again very much for having given us the opportunity to revise our manuscript ‘Cyclic peptide drugs approved in the last two decades (2001-2021)’. We found the reviewers' comments helpful to improve our review and have addressed all criticisms and followed all suggestions raised. Here we resubmit the amended manuscript as follows.

In particular, we adjusted the contents of the tables and figures by removing source information and adding the annual sales of 2020 for making the structure more logical and clearer towards the main points. We also changed orders of the mentioned drugs, discussed the biological functions of some drugs in more detail, explained the scope and perspectives of this review in more detail, rewrote parts of the perspective chapter in order to make it more logical, corrected several typos and grammatical errors, etc.

We provide below a point-by-point discussion of all the criticism and remarks, as well as explain the changes we made in the manuscript.

We hope that you and the reviewers will agree about our changes and we are looking forward to hearing from you.

Sincerely yours,

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Response to reviewer 1's comments:

1. Drugs (compounds) discussed in this review should be numbered 1,2,3,4... all the way to M (whatever M is). This way the reader knows what the number M is and they can also ensure that every compound has been discussed or at least mentioned.

Reply: We have now numbered the focus cyclic peptides 1-18 in Figures and Tables, and have cited each drug in the main text by the corresponding number. We examine every cyclic peptide drug from the perspective of its chemical structure, which is critical to its biological function and drug development. Other properties are also discussed, including the metabolizing properties, since we consider many ADMET hinders need to be resolved in order to promote the development of better cyclic peptide drugs.

2. There should be chem draw structure for every compound.

Reply: Chemdraw structure files have been uploaded for resubmission.

3. If something was approved and withdrawn -- the reader should know about it.

Reply: Peginesatide is the only cyclic peptide drug withdrawn in the past two decades. A chapter discussing the development and withdrawal of peginesatide is added, entitled "A lesson from the withdrawn cyclic peptide drug".

4. Money is important. Any mention of money in relation to approved drugs is always a good reminder to scientists that this business works because someone is willing to pay for it. It doesn't have to be comprehensive but the scientific reader needs to be reminded that certain drugs that didn't make any money eventually "failed after approval" and this is the sad reality of drug business.

Reply: In the tables, the 2020 annual sales of the discussed cyclic peptide drugs are summarized. The sales of many of the cited drugs, however, are not disclosed. Sales of recently approved drugs may not reflect the actual market recognition or efficacy, as a result of limited production and inadequate promotion resulting from a short on-market time. Several approved cyclic peptide drugs have really low sales in dead.


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Response to reviewer 1's comments:

1) The authors have restricted the review to clinically approved drugs, but many of the advances and modern methods they outline in the introduction and then detail in the main body and the conclusions are only applicable to peptides under investigation in clinical or pre-clinical trials and have not yet been realized in terms of approved drugs. Further, in the introduction the authors state the review is restricted to cyclic peptides between 5-20 residues. It is not clear why this limit has been applied, given insulin is mentioned as the first cyclic peptide drug, yet is comprised of >50 residues.

Reply: In order to better convey our intentions, we adjusted the text. It was discussed what can be learned from approved cyclic peptides, especially in terms of chemical modification and structural optimization applied for promoting the development of cyclic peptide drugs. This experience is valuable for the development of cyclic peptide drugs in the future when we apply modern peptide selection platforms, as discussed in the perspective chapter, for hit discovery and ligand optimization during the very early phases of cyclic peptide drug development. The last paragraph of the introduction is rewritten as follows:

“In this review, we summarize the discovery and development of cyclic peptides that have been discovered in the last two decades. Chemical structures, mechanisms of action and metabolic properties are analyzed to unveil the important factors for cyclic peptide drug development and utilization in clinical situations. We mainly focus on cyclic peptide therapeutics by excluding peptides with >20 amino acids that show properties similar to small proteins and peptidomimetics with <5 residues that show physical properties similar to small molecules. Taking advantage of many recently developed technologies of building cyclic peptide libraries with a diversity of billions by translation genetic variations, cyclic peptides with a length of this range can be routinely screened and rapidly synthesized for hit discovery and affinity maturation to obtain cyclic peptides suitable for drug development. The opportunities and perspectives for cyclic peptide drug development are also discussed.”

We believe peptides with fewer than 20 residues, which can be chemically synthesized routinely and rapidly in lab settings, can be the primary family of peptides for efficient drug development. The development of linear and hormone analogic peptide drugs, which mainly use biological production, has been intensively studied and has a different development trajectory compared with cyclic peptide drugs developed in recent years. To reflect our actual intentions, we revised the introduction of insulin as follows:

“Since insulin was first used in the clinic almost 100 years ago[1], the spectrum of potency, specificity, and safety of peptidic chain enhanced by cyclization has demonstrated the fundamental characteristics of cyclic peptides.”


2) The structure of the manuscript is confusing, with the peptides of interest divided into sections by their target; intracellular, extracellular, or microbial. But the authors also try to classify the compounds by their mode of production; natural products, semi-synthetic compounds, or synthetic.

Reply: The ‘source’ column was removed from the Tables for the sake of reducing confusion and increasing consistency of categories. However, the sources of the cyclic peptides mentioned in the text were kept. In accordance with the chapter titles, the discussed cyclic peptide drugs are classified according to their targets: human intracellular proteins (need to pass plasma membrane), human extracellular proteins (no need to pass through plasma membrane), and microbial proteins (another mode of interaction with plasma membrane). It is our hope that this organization will assist readers in choosing the primary category of the target protein that interests them. Over the history of cyclic peptide development, the source of cyclic peptides has evolved from natural sources, analogs of natural peptides, and in recent years, laboratory-produced non-natural peptides.


3) The authors state “peptide-based molecules with molecular weights >1000 Da are generally too large to be computationally calculated” but this is irrelevant as none of the approved drugs were designed through computational analysis.

Reply: The text has been amended to reflect our actual intentions. A major obstacle to the development of cyclic peptide drugs targeting intracellular proteins is getting the molecules past the plasma membrane protein. For small-molecule development, there are ready-to-use theories for calculating and predicting the membrane permeability and bioavailability properties. When peptides with a molecular weight > 1000, they show properties different from small molecules, and there is no general understanding of a mechanism that can guide the design of cell membrane-permeable peptides. As a result, we amend the text in the introduction of cyclic peptides "Targeting intracellular proteins" as follows:

“Developing cell-permeable cyclic peptides that can reach intracellular targets is a challenging task[10]. Unlike small molecules that enter cells primarily through passive diffusion, peptide-based molecules greater than 1000 Da have distinct physical properties, mechanisms, and cell permeability abilities, and currently available theories for improving ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of small molecules don't apply to the development of cyclic peptides[24]……”


4) The description of the biological activity of somatastatin at the top of column 2, page 5, should be incorporated earlier in the section on pasireotide.

Reply: Thank you very much for the suggestion. Somatastatin's description has been changed, and it now appears in the section of Pasireotide.


5) The section on melanocortin receptor agonists should be re-structured as it is not clear for which indication bremelanotide is approved. Further, the discussion of terlipressin in this section creates more confusion as it is not a melanocortin receptor agonist.

Reply: The sections about melanocortin receptor agonists were updated. In the section for Bremelanotide, more details of the targeted signaling pathway are discussed, as well as information about its medical use. The following was adjusted in the section of Bremelanotide:

“Activation of G-protein coupled MC receptors will cause increased intracellular production of cAMP, calcium mobilization and receptor internalization, and subsequently activates dopamine terminals in the medial preoptic area (MPOA) [93, 94]. Dopamine (DA) released in MPOA -mediates a variety of physiological effects, including the activation of sexual arousal……”

We also updated the Terlipressin section to clarify its indication. Terlipressin, an analog of Vasopressin, targets the V1 family of Vasopressin receptors. A description of Terlipressin's target protein was added to indicate similarity with Vasopressin drugs. In Table 2, the order of Terlipressin and Vasopressin is also adjusted to reflect the fact that Vasopressin has been used in the clinic for a longer period and was only recently re-authorized with a new drug application.


6) The section on antimicrobial agents is satisfactory, but none of these drugs have been approved more recently than 2014, so there is no new information.

Reply: Antimicrobial agents were examined from a different perspective by relating the chemical structure with biological functions. A summary of the important structural aspects for achieving the desired biological activities is provided, along with the mechanism of action. Cyclic peptides have a high potential for developing novel antimicrobial agents and are an essential part of peptide drug development. The experience of developing novel cyclic peptide antimicrobial agents is an important guide for future work.

7) The ‘Perspectives and conclusions’ sections introduce a lot of new information that is not relevant to the previous sections. For example, the passage “Directed evolutions with genetically displayed cyclic peptide recombinant libraries is increasingly playing more important roles in next-generation cyclic peptide drug discoveries. Display systems such as mRNA display, DNA display, and phage display offer the advantages of large library diversity and rapid screening, and have resulted in the discovery of a good portion of cyclic peptides in clinic development” may be true, but is not directly relevant to the approved drugs covered in this review. If the authors wish to include such modern technologies in this review, they should expand the scope of the review to peptides in clinical and pre-clinical development. Such an expansion of scope would be a major undertaking, but without it this manuscript is essentially covering material already well-reviewed in the literature.

Reply: We added more discussion in the perspectives chapter for making the review more logical. We added the following examples to the paragraph discussing lessons from the present cyclic peptide drug:

“In the past two decades, the primary trend in peptide drug discovery has been the shift of naturally isolated cyclic peptides toward cyclic peptide analogs optimized for improving potency, stability, and pharmacokinetic properties. By incorporating aromatic naphthalene and D-tryptophane into Lanreotide, its nanotubes of supramolecular packing were stabilized, which contributed to its extended half-life and ability to suppress hormone levels and activities. From a technical perspective, cyclic peptide drug development benefited from rapid lead discovery with adjustable and expandable optimization by chemical synthesis, which was the milestone in peptide drug development. The mutation of the lipophilic side chain of Oritavancin prolonged its half-life and enhanced coverage against several vancomycin-resistant bacteria. Fermentation of cyclic peptides also benefited from modern molecular biology technologies, and the primary sequences of enzymes could be rapidly mutated and optimized for achieving higher production yields. Increased expression of echinocandin B deacylase in the production host significantly increased transcription and bioconversion efficiency of Anidulafungin……”

Following the last important review of cyclic peptide drugs (Zorzi, A. et al., Curr Opin Chem Biol, 2017), four new cyclic peptide drugs (Trulance, Vyleesi, Imcivree, and Lupkynis) have been approved. Additionally, we emphasized the importance of absorption and distribution properties in a drug's approval from the point of view of the peptide structure. A discussion of present-day cyclic peptide development technologies is included, though none of them was applied to the development of the approved cyclic peptide drug. Because We believe these technologies will be widely applied for the development of cyclic peptide drugs of the next generation. The number of research groups focusing on developing these technologies is rapidly growing, and all of these efforts will not only lead to scientific discoveries but will also advance cyclic peptide drug development for improving the health conditions of the general public.

05-Nov-2021

Dear Professor Chen:

Manuscript ID: CB-ART-07-2021-000154.R1
TITLE: Cyclic peptide drugs approved in the last two decades (2001-2021)

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 all of my minor comments regarding the manuscript, and it presents with much better readability and understanding. The major comment, that the ‘Perspectives and conclusions’ sections introduces a lot of new information that is not relevant to the previous sections, has not been fully addressed, but to do so would require a substantially longer and re-written manuscript. Accordingly, I am happy to defer to the editor's decision regarding suitability for publication.