Recent Advances in PROTACs for Drug Targeted Protein Research
Round 1
Reviewer 1 Report
This is an interesting, important and niche-filling manuscript that deals one of the most recent developments of targeted drug therapy, PROTACs. These molecules achieve specific degradation of their targeted protein molecules. This approch has the potential to possibly target otherwise untargeteble proteins within the cell. The manuscipt provides exhaustive review oth the are, cerainly not restricted to onco/hematology or neurodegenerative disorders, the two main field of intensive research within PROTAC development.
The manuscript covers the entire field well and provides concise information to the readers. Unfortunately, frequently its language is sloppy, contains lab-slang (eg. non-lymphoma Hodgkin - such a disease does not exist with szótandards diagnostic criteria).
Summarily, it is a valuable manuscript that needs extensive improment in style and the use of English language.
Author Response
Thank you very much for your valuable opinions and we have revised the paper carefully. All the formats and relevant grammar, sentence errors in the article have been corrected.
Reviewer 2 Report
Review article: Recent Advances in PROTACs or Drug Targeted Protein Research.
Major Concern: The authors provide a very comprehensive overview of the published literature. However, they do not provide any additional analysis or new insights based on this literature as is required for a review article. Therefore in its current form it cannot be published as a review.
Specific concerns:
The introduction would benefit from a more in-depth discussion of the advantages PROTACs provide over both traditional and targeted chemotherapeutic targets and why they represent a better therapeutic strategy in some cases. Additionally, there is no discussion on the effect and importance of the linker region of the molecule, which has been found to be important for the activity of these molecules.
It would also be useful for there to be an introduction to the idea that many of the proteins for which PROTAC molecules have been developed have a significant scaffold function in addition and/or instead of an enzymatic activity which would be removed by the use of PROTAC molecule.
In the descriptions of the specific PROTAC target molecules, for the majority there is no discussion or description of the biological consequences of the degradation of the protein of interest.
In the brief introduction to each disease area very broad, often inaccurate, statements are made which do not add to the article and use emotive rather than scientific language e.g. line 66/67.
In places ambiguous statements are made e.g. line 224 “BCL-xL specific inhibitors target platelet toxicity, limiting their application in acute leukemia.” Do the authors mean that due to the role BCL-xL plays in platelet homeostasis, inhibition of BCL-xL results in ‘on-target’ toxicity leading to thrombocytopenia?
Line 136 “PROTAC technology may solve this poser” – this is not good English.
Line 597 doesn’t make sense – how can a specific level of degradation be dose dependent? Surely that level of degradation quoted 44% was at a specific dose?
Line 70 what do the authors mean by ‘non-pharmaceutical’?
The tables would benefit from a key to tell the reading what the different coloured parts of the molecule represent e.g. red – molecule to bind to POI, black – linker, blue – ligand of E3 ligase.
Throughout the article there are numerous typos with random capital letters in the middle of sentences, missing spaces, additional full stops etc.
In table 1 PROTAC 10 is miss labelled as targeting PIPK2 not RIPK2
PROTAC 55 does not appear to have a blue E3 ligand portion of the molecule?
Author Response
Major Concern: The authors provide a very comprehensive overview of the published literature. However, they do not provide any additional analysis or new insights based on this literature as is required for a review article. Therefore in its current form it cannot be published as a review.
Answer: Thank you very much for your kind suggestions. We discuss the application of PROTAC in cancer, immune diseases, neurodegenerative diseases, cardiovascular diseases and viral infections, and summarize and prospect its potential targets and indications. For example, we discussed that targeting ASK1 degradation through PROTAC molecules may become a new strategy for treating diseases such as Nash and DKD. This is a new target, and I hope it can bring inspiration to relevant researchers. In addition, we look forward to the development of PROTAC in the field of antiviral infection. So we think our review is also worth reading.
Specific concerns:
The introduction would benefit from a more in-depth discussion of the advantages PROTACs provide over both traditional and targeted chemotherapeutic targets and why they represent a better therapeutic strategy in some cases. Additionally, there is no discussion on the effect and importance of the linker region of the molecule, which has been found to be important for the activity of these molecules.
It would also be useful for there to be an introduction to the idea that many of the proteins for which PROTAC molecules have been developed have a significant scaffold function in addition and/or instead of an enzymatic activity which would be removed by the use of PROTAC molecule.
Answer: Thank you very much for your advice. It is necessary to discuss the advantages of PROTAC compared with conventional chemotherapy and targeted therapy and the role and importance of linker. Therefore, we added relevant discussion in the introduction section, where we also briefly explained that PROTAC can affect non-enzymatic function. This point was also analyzed in Conclusions and Prospects. "Third, PROTACs can affect non-enzymatic functions. Conventional small-molecule medications often work by stopping their targets' enzyme activity. Accumulating studies have shown that PROTACs have the potential to increase the "druggable Space "of targets and to regulate protease as well as non-enzyme functions." Can be easily viewed by using the Track Changes function in Word.
In the descriptions of the specific PROTAC target molecules, for the majority there is no discussion or description of the biological consequences of the degradation of the protein of interest.
Answer: Thank you very much for reminding us that it is very necessary to discuss the biological parameters of protein degradation, so we have added the biological parameters of specific PROTAC target molecules in the table.
In the brief introduction to each disease area very broad, often inaccurate, statements are made which do not add to the article and use emotive rather than scientific language e.g. line 66/67.
Answer: Thanks for your suggestion. We have carefully revised the paper to make the language more rigorous and scientific and avoid emotional language.
In places ambiguous statements are made e.g. line 224 “BCL-xL specific inhibitors target platelet toxicity, limiting their application in acute leukemia.” Do the authors mean that due to the role BCL-xL plays in platelet homeostasis, inhibition of BCL-xL results in ‘on-target’ toxicity leading to thrombocytopenia?
Answer: Thank you for your correction. We have revised the ambiguities in the article. Line 224 has been modified as "However, targeted, dose limiting drug formulation, bcl-Xl-specific inhibitors Leading to Thrombocytopenia, which limits their application in acute leukemia"
Line 136 “PROTAC technology may solve this poser” – this is not good English.
Line 597 doesn’t make sense – how can a specific level of degradation be dose dependent? Surely that level of degradation quoted 44% was at a specific dose?
Line 70 what do the authors mean by ‘non-pharmaceutical’?
Answer: Thank you very much for your reminding and correction. We have modified these mistakes. Line 136 has been modified as "PROTAC technology may solve this Dilemma". Line 70 has changed "non-pharmaceutical" to "Undruggable"; Line 597 has been modified to "Among them, the representative Compound PROTAC 62 (Table 3) can degrade more than 44% of GSK-3β", Easy to view with "Track Changes" in Word.
The tables would benefit from a key to tell the reading what the different coloured parts of the molecule represent e.g. red – molecule to bind to POI, black – linker, blue – ligand of E3 ligase.
Answer: Thank you for your correction. We have added relevant comments to the table
Throughout the article there are numerous typos with random capital letters in the middle of sentences, missing spaces, additional full stops etc.
In table 1 PROTAC 10 is miss labelled as targeting PIPK2 not RIPK2
PROTAC 55 does not appear to have a blue E3 ligand portion of the molecule?
Thank you for your correction. We have carefully revised the paper and changed Answer:"PIPK2" to "RIPK2" in Table 1. All the formatting and related grammatical and sentence errors in the paper have been corrected. In contrast to previous reviews, PROTAC 55 molecules use chloralkanes to covalently bond with HaloTag 7, an engineered bacterial dehalogenase, and are able to recruit POI to HaloTag 7-tagged E3 ligases, so PROTAC 55 has no E3 ligand component.
Round 2
Reviewer 1 Report
Improved manucript, I have no further concerns.
Author Response
Answer: Thank you very much for your reply. We have further revised and improved this paper. We hope that this paper can provide help to researchers in related fields.
Reviewer 2 Report
Although the authors have addressed most of my minor concerns there are still numerous typographical errors throughout the manuscript, with missing punctuation and random capital letters in the middle of sentences. There are also still sentences in the manuscript that are ambiguous and not written in good English.
Author Response
Answer: Thank you very much for your reminding and correction. We have modified these mistakes. We have also carefully revised the paper to make the language more rigorous and scientific
