Zika Virus Infection and Development of Drug Therapeutics

Round 1

Reviewer 1 Report

In this study, Guo et al. summarize the genome and structure of the Zika virus, the viral and transmission cycle, clinical manifestations, animal models, and antiviral drug development. The review is well performed and there are minor points that could improve the manuscript:

·       The authors mentioned in the text that ZIKV has 11 proteins; however later in the text refer to 3 structural proteins and 7 non-structural proteins. Please review sentences in lines 48-50, 54, and 82.

·        Figure 3. Please include a descriptive legend.

·     Figure 3. The authors may point out where the inhibitors/antivirals of ZIKV act during the ZIKV life cycle.

·        I would suggest the authors include cell lines used to study ZIKV. Some cell lines are briefly described in section 7, however, a section needs to be included before “6. Animal models of ZIKV”.

·        It would be of interest to add a table summarizing the antiviral strategies develop for ZIKV, including the mechanism of action.

·        In my opinion, the authors need to include a future perspective.

Author Response

Dear reviewer,

Thank you for the time and effort that have put into reviewing the previous version of the manuscript, your professional suggestion have enabled us to improve our work. Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Manuscript ID: applmicrobiol-1869055

Type of manuscript: Review

Title: Zika Virus infection and Development of Drug Therapeutics

Authors: Jiao Guo, Xi Ma, Xi Xu, Yan Guo, Bixuan Li, Meihua Wang, Yang Wang *

 

This work summarizes general findings and history of the Zika virus (chapters 1-4) and then reports on clinical manifestations and anti-ZIKV strategies (chapters 5-7). In particular, the chapter 7 summarizes specific drug development strategies and ongoing research results for each target molecule.

This reviewer would like to recommend this paper for publication in Applied Microbiology after necessary revisions are made adequately. My comments and suggestions are generally to the extent of minor revisions to publish in Applied Microbiology. This reviewer would like to recommend the authors retake the manuscript to add figures or tables.

 

(1) There is some redundancy between L336-345 and L366-373. If there is a difference in the experimental system or subject of the assay, it should be explained more clearly.

 

(2) Regarding the triangles marking the protease cleavage sites in Fig. 2(A), please insert a sentence explaining the difference between the white and black triangles. If it is a frameshift, please state so.

 

(3) If the mechanism of action or target molecule of the drug is clear, as in L208-216 and L236-240, please briefly point out the relationship in Fig. 3 and add a diagram showing the relationship between the molecules.

 

(4) A table that gives an overview of the contents of Chapter 7 would be reader-friendly.

 

(5) L401-402: This reviewer wonders why SARS and MERS are in the authors' comments but not SARS-2 (COVID-19).

 

typos

L49: yield 11 protein à 11 proteins

L315: “TPB”: Provide the name of the compound or a description of its properties.

L331: EE. coli à E. coli

Author Response

Dear Reviewer,

We do appreciate your professional comments about this manuscript from the bottom of our heart. We have revised and improved our manuscript according to your helpful comments. Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

The paper entitled "Zika Virus infection and Development of Drug Therapeutics" aimed to summarize the knowledge about ZIKV structure, transmission cycle, clinical manifestations, animal models, and development of antivirals. The proposed work is exciting and would contribute to improving the knowledge about ZIKV, which threatens global human health. However, the work does not bring new information to the research field and does not show its difference from other published works present in the literature. In the body of the paper, several problems would need to be addressed, such as gaps in knowledge, unclear sentences, repetition of information, and lack of references. In addition, the figures would need proofreading and editing. Taken together, these issues take away confidence in the content presented. I believe that the paper should be rejected in its current version.

Here are some related and already published articles:

• https://doi.org/10.3390/ijms22010035
• https://doi.org/10.1016/j.virol.2020.01.015

More detailed feedback follows:

Abstract

Lines 14-15: "Given the public health crisis related to the ongoing outbreak," Is an outbreak currently occurring? Please explain the current situation in the introduction and insert references.

Introduction

Lines 28-30: "and has been detected in mosquitoes and humans throughout Southeast Asia and African countries since then." Citation is needed here.

Lines 31-32: "it was understudied until an outbreak in French Polynesia from 2013 to 2014 and an epidemic in Brazil from 2015 to 2016 (Figure 1) (4,5)." In addition, it is essential to mention the Yap Island outbreak.

Lines 32-33: "In 2016, the World Health Organization declared the ZIKV epidemic as an international health emergency." Citation is needed here.

Line 40: "and its emergence as a global health." Please clarify what you meant here.

Genome and structure of ZIKV

Figure 1a. Does only the viral protease cleave the polyprotein? Please clearly represent the cleavage sites by the viral protease, the host protease, and the unknown protease.

Line 48: "Figure 2. ZIKV polyprotein and protease cleavage sites." The title of the figure does not encompass what is shown in the figure as a whole.

Lines 51-53: "(B). I believe you would need to improve the score here. The table summarizes structural and no structural ZIKV proteins. The name and biology function are shown for each protein."

Lines 60-62: "NS1 is the major target for neutralizing and protective antibodies. It is responsible for ZIKV infection and hosts immune response." This sentence needs to be revised. Are there references to support these statements? Please rewrite the function of NS1 more clearly, and add the appropriate references.

Lines 62-63: "NS2A is a hydrophobic protein that participates in the process of viral replication complex assembly and secretion." NS2A participates in the secretion of what? Please explain more clearly.

Lines 63-65: "NS2B and NS3 are anchored to the endoplasmic reticulum membrane as a heterodimer, and they have a lyase function at the junctions of NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5 (13, 14)." Please revise this sentence and better write the function of this viral protease. Does NS2B-NS3 cleave only in these regions?

Why didn't you mention the function of NS4B? Likewise, it is essential to mention the functions of the prM and E proteins. In this topic, structural and nonstructural protein functions must be presented clearly.

The viral life cycle of ZIKV

Line 74: "3. The viral life cycle of ZIKV." I believe that the title of this topic could be changed.

Lines 77-78: "Briefly, the E proteins participated in the attachment of the virus particles to receptors on the cell membrane..." I believe that sentence would be better in the singular.

Line 78: "in the low pH environment." What does this information mean? Please clarify.

Lines 85-87: "Subsequently, the viral positive-sense RNA is used as a template to generate negative-sense RNA. It could be recruited for new rounds of translation/replication or incorporated into the virus particles (20)." Please rewrite how the process of translation and replication of the viral genome occurs.

Line 87: "Assembled virions enter..." How does the assembly of the new viral particles take place? Please clarify.

Figure 3. The figure needs to be revised and edited. Please add a clear and succinct caption.

The transmission cycle of ZIKV

Lines 92-96: "ZIKV can be divided based on two different transmission modes in evolution and ecology, namely forest transmission and urban transmission. The former refers to the transmission of ZIKV between vertebrates and arboreal mosquitoes, whereas the latter refers to the transmission of ZIKV between humans and Aedes albopictus in the environment (21)." Hard to understand sentences. Please rewrite.

Lines 92-96: "ZIKV can be divided based on two different transmission modes in evolution and ecology, namely forest transmission and urban transmission. The former refers to the transmission of ZIKV between vertebrates and arboreal mosquitoes, whereas the latter refers to the transmission of ZIKV between humans and Aedes albopictus in the environment (21)." Hard to understand sentences. Please rewrite.

Line 107: "Further, Brazil published a case report of ZIKV transmission through blood transfusion;" Citation is needed here.

Clinical manifestations of ZIKV disease

Lines 117-119: "ZIKV infection in adults, compared with encephalitis flaviviruses such as JEV,  WNV, and TBEV, which are less invasive and generally do not cause symptoms of encephalitis and meningitis." Hard to understand the sentence. Please rewrite.

Lines 124-125: "In recent years, the outbreak of ZIKV infections in North America and Brazil has caused great public panic." What years are you referring to? Please add references.

Lines 126-128: "sexual transmission, which can destroy the placental function of pregnant women, causing fetal intrauterine growth restrictions, congenital malformation, microcephaly, and even death (30). ZIKV can be transmitted from mother to child;" This information has already been written in the previous topic (Lines 101-106).

Antiviral drug advancement

Lines 220-222: "Several entry receptors, including transmem- 220 brane protein TIM-1, the innate immune receptor DC-SIGN, and TAM receptors (TYRO3, 221 AXL, and MER), have been reported to facilitate ZIKV entry and infection (19)." Repetition of information. This information has already been written in topic 3 (lines 79-80).

Lines 228-235: "The natural product nanchangmycin, an inhibitor of AXL, was generated in Streptomyces nanchangensis. Rausch et al. screened a library of bioactive compounds with antiviral activity against ZIKV infection in three distinct cell lines and revealed that nanchangmycin abrogates viral internalization through clathrin-coated vesicles. Moreover, the authors showed that nanchangmycin also suppresses WNV, DENV, and Chikungunya virus, which employs similar host pathways for entry. These studies will ultimately inform therapeutic strategies for antiviral interventions against important flaviviruses and alphaviruses." References are lacking for this content.

In this topic, it is essential to describe which antivirals are being studied, their current status, promising results, and the limitations that each one presents. The most advanced and promising antiviral should be highlighted.

 Conclusion

The conclusion needs to be revised and rewritten. Please write a more succinct conclusion, bringing a reflection on the content presented in the article and its prospects.

 

 

Author Response

Dear Reviewer 3:

We sincerely appreciate your professional comments about our work. We have revised and improved our manuscript according to your so valuable advices. Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

The revised version greatly improved the manuscript which can now be published.