Natural Peptide Toxins as an Option for Renewed Treatment of Type 2 Vasopressin Receptor-Related Diseases

Round 1

Reviewer 1 Report

This is a very interesting review that describes how natural peptide toxins, known to act selectively and at low concentration on their receptor target, could offer new therapeutic options. It focusses mainly on the blockade of the vasopressin V2 receptor for which the author has developed a series of drugs called "mambaquaretins", based on the venom of a Mamba snake. Vasopressin's action on this receptor is involved in the control of fluid balance but also in several pathologic conditions for which a very selective antagonism could represent an important piece of the therapeutic armamentarium.  

 

I have two major comments and several other minor comments.

 

Major comments

 

1. An important information is missing about the V2R.

V2R is also localized in the vascular endothelium. In response to AVP, the endothelium, via V2Rs, induces the release of NO that can vasodilate the smooth muscle cells that lie just below the endothelium. The smooth muscle cells expresses V1a receptors so that vasopressin might also induce a vasoconstriction. This dual regulation may explain why the role of vasopressin in the regulation of blood pressure has been so difficult to evaluate. It also explains why a relatively high dose of dDAVP induced a marked fall in blood pressure was reported by Bichet et al in "Desmopressin in Bleeding Disorders. Plenum Press, New York, NY: 1993; 89–99"  but not well understood at that time. This data is reproduced in figure 1, right panel in:

Bardoux P, Bichet DG, et al. Nephrol Dial Transplant. 2003 Mar;18(3):497-506. doi: 10.1093/ndt/18.3.497. PMID: 12584270

 

See a few other papers below (and there are many more).

 

Juul KV, Bichet DG, Nielsen S, Nørgaard JP. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol. 2014 May 1;306(9):F931-40. doi: 10.1152/ajprenal.00604.2013. Epub 2014 Mar 5. PMID: 24598801.

 

Medina P, Segarra G, Vila JM, Chuan P, Domenech C, Lluch S. V2-receptor-mediated relaxation of human renal arteries in response to desmopressin. Am J Hypertens. 1999 Feb;12(2 Pt 1):188-93. doi: 10.1016/s0895-7061(98)00230-1. PMID: 10090347

 

Kaufmann JE, Iezzi M, Vischer UM. Desmopressin (DDAVP) induces NO production in human endothelial cells via V2 receptor- and cAMP-mediated signaling. J Thromb Haemost. 2003 Apr;1(4):821-8. doi: 10.1046/j.1538-7836.2003.00197.x. PMID: 12871421

 

2. A problem with the reference list.

A number of references cited in the text are not found in the list at the end of the MS. And some references in the list are not always presented appropriately. May be there was a problem with the reference management software? See more comments about references in the detailed comments below.

 

Detailed comments

 

Introduction

About in the middle: heart (instead of hart)

Last line: It's probably better to write "about animal toxins..." instead of "of animal toxins...."

 

2.1. V2R structures

Line 10 of first paragraph. ... vasopressin-sensitive receptors. (no "s" for sensitive). When two names follow each other, the first one does not take a plural "s".

Last line of first paragraph. Could you provide a reference for "Lys100 is unique in human V2R"?

 

2.3. V2R expression and functions

Second paragraph. Could you indicate the species studied, as there may be a few species differences in the localization of the V2R along the nephron.

A few lines after the beginning of this section, write "the epithelial sodium channel ENaC...." (not just "the channel ENaC").

 

A little further down, about AQP2. I did not read the very recent literature, but I think that the AQP2 molecules are NOT translocated from intracellular vesicles to the apical membrane. I think the vesicles themselves, located subapically and containing many AQP2 molecules, are fused with the apical membrane. When AVP stimulation stops, these vesicles can be re-internalized. Please check.

Replace "Urine water" by "Luminal fluid".

 

About V2R receptors in the lung. You may indicate that these receptors are very important in the fetal lung. AVP contributes to the reabsorption of alveolar fluid in the hours following birth. It stimulates ENaC, thus promoting sodium reabsorption, and water follows. See for example reference below.

Evers KS, Wellmann S. Arginine Vasopressin and Copeptin in Perinatology. Front Pediatr. 2016 Aug 2;4:75. doi: 10.3389/fped.2016.00075. PMID: 27532032; PMCID: PMC4969663

 

In this section, add some information about V2R in the endothelium (see above).

 

Last paragraph (and page 4 middle and possibly other places in the MS). Be consistent in writing dDAVP. In some places your wrote DDAVP, in others dDAVP. Actually, the first d should not be capitalized. It means "de-amino". The second D means D-arginine (as opposed to L-arginine).

 

Write "pulmonary metastase proliferation" (no "s" for metastase). When two names follow each other, the first one does not take a plural "s".

 

About "arginine-vasopressin". It may be useful (although not really necessary) to explain why the word "arginine" needs to be mentioned in the name of this hormone. It is because this hormone is a "lysine-vasopressin" in the pig and related mammals (one amino acid substitution). LVP binds to each AVP receptors with the same affinity as AVP. For many years, before synthetic AVP was available, investigators used LVP extracted from the pig hypophysis.

 

2.4. AVP secretion

Instead of "Robertson 1976" or in addition to this reference, you may cite the following reference.

Zerbe RL, Robertson GL. Osmoregulation of thirst and vasopressin secretion in human subjects: effect of various solutes. Am J Physiol. 1983 Jun;244(6):E607-14. doi: 10.1152/ajpendo.1983.244.6.E607. PMID: 6407333.

 

In the paragraph at the top of page 4/12 about anticipation, you may cite the following reference.

Bichet DG. Regulation of Thirst and Vasopressin Release. Annu Rev Physiol. 2019 Feb 10;81:359-373. doi: 10.1146/annurev-physiol-020518-114556. PMID: 30742785.

 

 Page 4/12, second paragraph. If you cite "copeptin", you need to say it is considered to be a a valid marker of vasopressin. Cite for example:

Bankir L, Bichet DG, Morgenthaler NG. Vasopressin: physiology, assessment and osmosensation. J Intern Med. 2017 Oct;282(4):284-297. doi: 10.1111/joim.12645. Epub 2017 Jul 26. PMID: 28649750.

 

Or : Christ-Crain M, Morgenthaler NG, Fenske W. Copeptin as a biomarker and a diagnostic tool in the evaluation of patients with polyuria-polydipsia and hyponatremia. Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):235-47. doi: 10.1016/j.beem.2016.02.003. Epub 2016 Feb 16. PMID: 27156761

 

Or : Evers KS, Wellmann S. Arginine Vasopressin and Copeptin in Perinatology. Front Pediatr. 2016 Aug 2;4:75. doi: 10.3389/fped.2016.00075. PMID: 27532032; PMCID: PMC4969663

 

3. V2R, an enexploited....

Third paragraph. You may briefly cite (if you like) Satavaptan (Sanofi) and Lixivaptan (Palladio Biosciences) both of which were used in clinical trials (see https://clinicaltrials.gov) but were abandonned (Lixivaptan very recently).  

 

Fourth paragraph, first line. Very minor detail. Concentration" would be more appropriate than level (although level is often used). Solutes do not have a level (which is supposed to be a 2D flat surface) in the blood but have a "concentration" in the blood.

Fourth paragraph, second line. "in other" seems strange in this sentence. Is a word missing?

 

Page 5, top. May be you could mention that, in most countries,tolvaptan is used only in patients with "rapidly progressive" ADPKD, not in all patients with ADPKD.

 

4. Natural peptide toxins....

First paragraph, third line. You probably mean "wide", not wild.

Page 5, 7lines before the end. You probably mean "compared" (not compare).

Page 5, last line. You probably mean "supported" (not support).

Bottom page 6. You may introduce the new word "mambaquaretin" before mentioning "8 other mambaquaretins".

 

5.1. In vivo activity....

Third line. You may introduce the term "aquaresis" instead of diuresis. Many papers now mention "aquaretics" for drugs that affect directly water excretion without increasing solute (mainly sodium) excretion, as opposed to "diuretics" which primarily affect sodium transport and secondarily water.

Last two lines. Reword the sentence with the word "mice" after the information about the "dose per mice". I suggest writing: Mice, treated daily by 12 µg MQ1 i.p. for 99 days, developed 30% less cysts... This would be easier to read.

 

6. Discussion.....

Second paragraph. Instead of "all hope is not lost", I suggest to write a much more positive sentence: "hope is permitted".

Paragraph starting with "MQ1, derived.....". The first sentence does not seem correct. I assume "combing" should be replaced by "combines".

Bottom of page 8. Toxin activities (toxin without "s"). .... combined with high selectivity and affinity are associated.... (add the words "high" and "are").

 

Reference list

I did not check all the references that are cited in the text, but in several cases I did not find the corresponding reference. A few examples below which are missing in the reference list.

Newman and Cragg, 2016 (beginning of discussion)

Furman, 2012 (middle page 8)

Bea et al, 2022 (middle of page 8)

Reynaud et al, 2022 (bottom of page 8)

Lipinsky 2016

and several others (I think mainly in the discussion, but may be not only).

 

A few references are not adequately presented.

--- Does Baelen et al, 2023 (bottom page 8) correspond to Baelen et al, 2022 in the reference list? In another place, it is cited as "van Baelen et al, 2022".

--- For Ref 52,  the first word "Peter" is likely the given name and not the last name of the first author. Thus, the reference is misplaced by alphabetic order.

 

Does the journal recommandations require to number the references in the reference list in spite of the fact they are listed by alphabetic order? Usually, numbers are not needed in that case. However, in reviews (in which a large number of references are cited) it is easier for the readers to find the references cited along the text if they are cited in order of appearance rather than by alphabetical order. What are the recommendations of the journal?

 

Author Response

My replied is the word document 

Author Response File: Author Response.docx

Reviewer 2 Report

The review by Giles is excellent and very informative. I have only two comments: A figure illustrating the structure of the V2 receptor and associated proteins named in the section describing the V2 receptor would be helpful. The statement that "all vaptans are hepatotoxic, tolvaptan (Otsuka Pharma) being less than the others" is not correct. If the author believes that the statement is correct, a supportive reference should be provided.

The topic is relevant for the journal.
It is comprehensive and up to date and the references are appropriate.

Author Response

My replied is the word document 

Author Response File: Author Response.docx