Non-Analog Compounds to Sialic Acid as Inhibitors of Influenza Virus Neuraminidase: An Underexplored Approach for Novel Antivirals―Systematic Review
, Carolina Jasso-Miranda 2, Virginia Sedeño-Monge 3 and Gerardo Santos-López 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn their article ”Non-Analog Compounds to Sialic Acid as Inhibitors of Influenza Virus Neuraminidase: An Underexplored Approach for Novel Antivirals “ authors present a review focused on alternative compound classes that are not analogous to sialic acid. The aim of the article is to discuss potential prospects for novel influenza antivirals, which inhibit the activity of viral neuraminidase in vitro, viral replication in cell culture, or animal models.
Finding and developing antiviral drugs is very important, especially considering the rapid mutation of the virus and the potential danger of a new pandemic.
In my opinion, the manuscript gives us a summary of available antivirals as well as new perspectives to think about. However, it needs some adjustments.
Results.
The table in supplementary material should be named and numbered.
Most the information in first paragraph, page 3, lines 102-107 is more proper for Section Materials and Methods.
Discussion.
Second paragraph, page 5, lines 145-150 is more proper for section Results.
Page 7, line 171 add the name of the protein where the evaluated mutations were found.
Lines 179-182 the paragraph is for the section Results.
Page 8, lines 232-235 cite the authors.
Author Response
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Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe paper by Márquez-Domínguez et al describes a literature review of the anti-influenza activity of non-sialic acid derivatives. While the paper appears to have done a fairly comprehensive job of identifying compounds of interest, the authors do very little with the information other than summarizing the data.
For example, the crystal structures of neuraminidase from various influenza strains have been extensively studied using X-ray crystallography and other structural biology techniques. While the authors do bring up the idea of the active site on page 7, they clearly have not done any structural analysis of the identified compounds. A structural analysis of the selected compounds might produce more profound insights that could guide future medicinal chemistry efforts. This is a significant weakness of the paper.
Another significant weakness is the authors did not provide any additional information on the compounds with activity <1uM. For example, Quercetin has been extensively studied in humans but the authors provided no discussion or references to the human safety or pharmacokinetics. It has also been studied in humans as a treatment for influenza (Heinz SA, Henson DA, Austin MD, Jin F, Nieman DC. Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacol Res. 2010;62(3):237-242. doi:10.1016/j.phrs.2010.05.001). The authors should include some brief summary of any known clinical data for the identified compounds.
Author Response
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Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors review articles from 2015 to 2021 for neuraminidase inhibitors essential for treating influenza virus. However, the influenza virus’s genetic variability leads to the emergence of drug -resistance mutations, particularly at the enzyme’s active site where these inhibitors bind, as they resemble sialic acid. Exploring alternative compounds that do not mimic sialic acid but can inhibit neuraminidase activity can pave the way for designing novel antiviral agents against influenza was the main scope of the review.
Some specific comments:
From line 171 to 177: please cite reference
Line 199-201- Was there any specific mechanism described in the literature which contribute to the 11 compounds higher EC50 values over IC50 values apart from NA inhibition?
Line 232 -235- Cite reference for puerarin, CHA and errKPAQP even if references are mentioned later.
Line 242-248- In this study, how was the CHA-efficacy comparable to oseltamivir or zanamivir?
Author Response
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Author Response File: Author Response.pdf
Reviewer 4 Report
Comments and Suggestions for AuthorsThe review covers 31 works that study the compounds that inhibit the activity of viral neuraminidase and have antiviral activity. The article may be useful for those working in this field, especially the extensive table in Supplementary Materials listing compounds and their main characteristics, with links to related work. Specific notes in the attached file
Notes:
1) Line 113 Table 1.
The caption under Table 1 is not complete, but the missing explanations are in the caption under Figure 2. This should be mentioned in the signature under Table 1
No mutations are indicated in the “Virus strain” column for compound 114.
It is necessary to indicate in which system the in vitro experiments were carried out and on which animals the in vivo experiments were carried out
2) Line 113 Table 1. And line 119-120 and 123-124
Lines 119-120 and 123-124 state that: "regarding the influenza A viruses used in the studies, the majority focused on the human serotype H1N1, while only one compound was tested against H3N2”; and “It is important to note that there is no available evidence on the selected compounds regarding non-human viral subtypes, such as avian or porcine strains ". However, Table 1 list two H3N2 viruses (A/WA/01/2007 (H3N2) and A/Beijing/32/92 (H3N2), and one H5N1 virus (A/Vietnam/1203/), which is actually a chicken virus, although isolated from humans. In addition, a number of strains belonging to the subtypes H5N1, H9N2 and H7N9 are listed in the supplementary.
3) Line 197: The specific viral strain used in this study was not specified [22].
Since compound 186 was tested only on one strain (see Figure 2), the viral strain is A/WA/01/2007 (H3N2), as well as in inhibition study
4) Section 4.2 and 4.3.
These sections list the names of the substances, but do not list their IDs. To compare the text with Table 1, you have to find these compounds in supplemental materials. For the convenience of the reader, you need to provide both names and IDs.
5) Line 251: “was designed to mimic the binding pocket of oseltamivir in influenza neuraminidase”.
This is not very clear. The original article puts it this way: “octapeptide (errKPAQP) … originating from mimicking the binding pocket of oseltamivir in neuraminidase, as a potent peptide neuraminidase inhibitor”.
Author Response
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Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors have adequately addressed the issues raised during my review.
