Dynamic behavior of Dengue and Zika viruses NS1 protein reveals monomer–monomer interaction mechanisms and insights to rational drug design

Gonçalves, Ricardo Lemes; Sussuchi, Luciane; Moreli, Marcos Lázaro; Mottin, Melina; Andrade, Carolina Horta; Pereira, Maristela; Silva, Roosevelt Alves da

doi:10.1080/07391102.2019.1677504

Cited by 15 publications

(25 citation statements)

References 15 publications

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“…The NS1 ZIKV dimer is considered as the functional unit, but the monomeric form has already been observed. 38 Therefore, we explored both oligomeric states in order to better decipher the role of the monomer unit in the dimer dynamics and also the role of the sequence itself by the dimeric analysis. Besides the overall dynamics features, we also focused on functional regions that we previously examined indepth, namely, the monomer−monomer interface, the epitope sites, and the membrane binding region.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Actually, this is supported by several recent studies that examined NS1 proteins from DENV and ZIKV by using constant-charge MD simulations, where interesting local differences were found for the monomer−monomer interface, despite an extremely wellpreserved fold. 38 Whether these differences at the dynamical level hold good at the intraspecific level, specifically for the ZIKV proteins NS1 UG and NS1 BR , is the challenging question that we have addressed in detail in the present work. With this aim, we used both all-atoms (AA) and coarse-grained (CG) classical MD simulations that have already proved to be quite efficient in several previous computational studies of other viral proteins.…”

Section: ■ Introductionmentioning

confidence: 92%

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How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence

Cuevas

Silva

Etchebest

2021

J. Chem. Inf. Model.

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Viruses can impact and affect human populations in a severe way. The appropriate differentiation among several species or strains of viruses is one of the biggest challenges for virology and infectiology studies. The detection of measurables-quantified discrepancies allows for more accurate clinical diagnoses and treatments for viral diseases. In the present study, we have used a computational approach to explore the dynamical properties of the nonstructural protein 1 from two strains of Zika virus. Our results show that despite a high sequence similarity, the two viral proteins from different origins can exhibit significant dissimilar structural dynamics, which complement their reported differential virulence. The present study opens up new ways in the understanding of the infectivity for these biological entities.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 92%

How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence

Cuevas

Silva

Etchebest

2021

J. Chem. Inf. Model.

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“…His26 and Trp28 putatively interact with ≥ 2 peptides and are located in the β-roll domain (amino acid residues 1-29), which is likely involved in NS1 dimerization and association with ER membrane and other viral transmembrane proteins 18,19 . A hydrophobic pocket involved in the monomer-monomer interaction of the DENV NS1 protein was also proposed in a recent study as a target for drug design to disrupt the structure of DENV NS1, particularly in the region consisting of Phe20, Ile21, and Trp201 75 . Furthermore, we found Arg192 to be recognized by peptides 4 and 10 in the β-ladder domain close to Lys189, which is a critical amino acid residue for efficient DENV RNA replication 19,20 .…”

Section: Scientific Reports |mentioning

confidence: 97%

Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production

Songprakhon

Thaingtamtanha

Limjindaporn

et al. 2020

Sci Rep

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Viruses manipulate the life cycle in host cells via the use of viral properties and host machineries. Development of antiviral peptides against dengue virus (DENV) infection has previously been concentrated on blocking the actions of viral structural proteins and enzymes in virus entry and viral RNA processing in host cells. In this study, we proposed DENV NS1, which is a multifunctional nonstructural protein indispensable for virus production, as a new target for inhibition of DENV infection by specific peptides. We performed biopanning assays using a phage-displayed peptide library and identified 11 different sequences of 12-mer peptides binding to DENV NS1. In silico analyses of peptide-protein interactions revealed 4 peptides most likely to bind to DENV NS1 at specific positions and their association was analysed by surface plasmon resonance. Treatment of Huh7 cells with these 4 peptides conjugated with N-terminal fluorescent tag and C-terminal cell penetrating tag at varying time-of-addition post-DENV infection could inhibit the production of DENV-2 in a time-and dosedependent manner. The inhibitory effects of the peptides were also observed in other virus serotypes (DENV-1 and DENV-4), but not in DENV-3. These findings indicate the potential application of peptides targeting DENV NS1 as antiviral agents against DENV infection. Dengue virus (DENV) infection is a major and increasing public health problem worldwide. There are approximately 390 million infections, 500,000 severe cases with hospitalization, and a 2.5% mortality rate each year 1,2. Although the majority of individuals experiencing DENV infection are asymptomatic, approximately one-fourth of the infected cases develop a wide range of clinical manifestations of dengue disease with unclear pathogenic mechanisms 3,4. To date, there is no specific anti-viral drug available for the treatment of DENV infection. A licensed dengue vaccine also has some limitations for use in naïve individuals not previously infected by DENV and in children less than 9 years of age 5,6. Consequently, the development of an alternative strategy to combat DENV infection and severe dengue is still needed. DENV is a positive, single-stranded, enveloped RNA virus belonging to the family Flaviviridae, and it has 4 distinct serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) 7. Infection with any DENV serotype can generate

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“…Molecular dynamics (MD) simulations have been widely used to understand the behavior of proteins in solution, as well as extract relevant information associated with their functions (Childers & Daggett, 2017 ). In our recent work it has been possible to understand important mechanisms involved in the stability of non-structural proteins of others viral species (Gonçalves et al., 2019 ; Menezes et al., 2019 ). Thus, in order to study dynamics of nsp1 from SARS-CoV-2, its structure was taken to MD simulation using GROMACS 5.1.2 software (Abraham et al., 2015 ) in AMBER ff99SB-ILDN force field.…”

Section: Methodsmentioning

confidence: 99%

Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

Silva

2020

Journal of Biomolecular Structure and Dynamics

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Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19. Communicated by Ramaswamy H. Sarma

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Dynamic behavior of Dengue and Zika viruses NS1 protein reveals monomer–monomer interaction mechanisms and insights to rational drug design

Cited by 15 publications

References 15 publications

How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence

How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence

Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production

Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

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