Cargando…

A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis

Shigella species account for the second-leading cause of deaths due to diarrheal diseases among children of less than 5 years of age. The emergence of multi-drug-resistant Shigella isolates and the lack of availability of Shigella vaccines have led to the pertinence in the efforts made for the devel...

Descripción completa

Detalles Bibliográficos
Autores principales: Palit, Parag, Chowdhury, Farhana Tasnim, Baruah, Namrata, Sarkar, Bonoshree, Mou, Sadia Noor, Kamal, Mehnaz, Siddiqua, Towfida Jahan, Noor, Zannatun, Ahmed, Tahmeed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8950558/
https://www.ncbi.nlm.nih.gov/pubmed/35335300
http://dx.doi.org/10.3390/molecules27061936
_version_ 1784675170161524736
author Palit, Parag
Chowdhury, Farhana Tasnim
Baruah, Namrata
Sarkar, Bonoshree
Mou, Sadia Noor
Kamal, Mehnaz
Siddiqua, Towfida Jahan
Noor, Zannatun
Ahmed, Tahmeed
author_facet Palit, Parag
Chowdhury, Farhana Tasnim
Baruah, Namrata
Sarkar, Bonoshree
Mou, Sadia Noor
Kamal, Mehnaz
Siddiqua, Towfida Jahan
Noor, Zannatun
Ahmed, Tahmeed
author_sort Palit, Parag
collection PubMed
description Shigella species account for the second-leading cause of deaths due to diarrheal diseases among children of less than 5 years of age. The emergence of multi-drug-resistant Shigella isolates and the lack of availability of Shigella vaccines have led to the pertinence in the efforts made for the development of new therapeutic strategies against shigellosis. Consequently, designing small-interfering RNA (siRNA) candidates against such infectious agents represents a novel approach to propose new therapeutic candidates to curb the rampant rise of anti-microbial resistance in such pathogens. In this study, we analyzed 264 conserved sequences from 15 different conserved virulence genes of Shigella sp., through extensive rational validation using a plethora of first-generation and second-generation computational algorithms for siRNA designing. Fifty-eight siRNA candidates were obtained by using the first-generation algorithms, out of which only 38 siRNA candidates complied with the second-generation rules of siRNA designing. Further computational validation showed that 16 siRNA candidates were found to have a substantial functional efficiency, out of which 11 siRNA candidates were found to be non-immunogenic. Finally, three siRNA candidates exhibited a sterically feasible three-dimensional structure as exhibited by parameters of nucleic acid geometry such as: the probability of wrong sugar puckers, bad backbone confirmations, bad bonds, and bad angles being within the accepted threshold for stable tertiary structure. Although the findings of our study require further wet-lab validation and optimization for therapeutic use in the treatment of shigellosis, the computationally validated siRNA candidates are expected to suppress the expression of the virulence genes, namely: IpgD (siRNA 9) and OspB (siRNA 15 and siRNA 17) and thus act as a prospective tool in the RNA interference (RNAi) pathway. However, the findings of our study require further wet-lab validation and optimization for regular therapeutic use for treatment of shigellosis.
format Online
Article
Text
id pubmed-8950558
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-89505582022-03-26 A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis Palit, Parag Chowdhury, Farhana Tasnim Baruah, Namrata Sarkar, Bonoshree Mou, Sadia Noor Kamal, Mehnaz Siddiqua, Towfida Jahan Noor, Zannatun Ahmed, Tahmeed Molecules Article Shigella species account for the second-leading cause of deaths due to diarrheal diseases among children of less than 5 years of age. The emergence of multi-drug-resistant Shigella isolates and the lack of availability of Shigella vaccines have led to the pertinence in the efforts made for the development of new therapeutic strategies against shigellosis. Consequently, designing small-interfering RNA (siRNA) candidates against such infectious agents represents a novel approach to propose new therapeutic candidates to curb the rampant rise of anti-microbial resistance in such pathogens. In this study, we analyzed 264 conserved sequences from 15 different conserved virulence genes of Shigella sp., through extensive rational validation using a plethora of first-generation and second-generation computational algorithms for siRNA designing. Fifty-eight siRNA candidates were obtained by using the first-generation algorithms, out of which only 38 siRNA candidates complied with the second-generation rules of siRNA designing. Further computational validation showed that 16 siRNA candidates were found to have a substantial functional efficiency, out of which 11 siRNA candidates were found to be non-immunogenic. Finally, three siRNA candidates exhibited a sterically feasible three-dimensional structure as exhibited by parameters of nucleic acid geometry such as: the probability of wrong sugar puckers, bad backbone confirmations, bad bonds, and bad angles being within the accepted threshold for stable tertiary structure. Although the findings of our study require further wet-lab validation and optimization for therapeutic use in the treatment of shigellosis, the computationally validated siRNA candidates are expected to suppress the expression of the virulence genes, namely: IpgD (siRNA 9) and OspB (siRNA 15 and siRNA 17) and thus act as a prospective tool in the RNA interference (RNAi) pathway. However, the findings of our study require further wet-lab validation and optimization for regular therapeutic use for treatment of shigellosis. MDPI 2022-03-17 /pmc/articles/PMC8950558/ /pubmed/35335300 http://dx.doi.org/10.3390/molecules27061936 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Palit, Parag
Chowdhury, Farhana Tasnim
Baruah, Namrata
Sarkar, Bonoshree
Mou, Sadia Noor
Kamal, Mehnaz
Siddiqua, Towfida Jahan
Noor, Zannatun
Ahmed, Tahmeed
A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
title A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
title_full A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
title_fullStr A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
title_full_unstemmed A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
title_short A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
title_sort comprehensive computational investigation into the conserved virulent proteins of shigella species unveils potential small-interfering rna candidates as a new therapeutic strategy against shigellosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8950558/
https://www.ncbi.nlm.nih.gov/pubmed/35335300
http://dx.doi.org/10.3390/molecules27061936
work_keys_str_mv AT palitparag acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT chowdhuryfarhanatasnim acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT baruahnamrata acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT sarkarbonoshree acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT mousadianoor acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT kamalmehnaz acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT siddiquatowfidajahan acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT noorzannatun acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT ahmedtahmeed acomprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT palitparag comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT chowdhuryfarhanatasnim comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT baruahnamrata comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT sarkarbonoshree comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT mousadianoor comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT kamalmehnaz comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT siddiquatowfidajahan comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT noorzannatun comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis
AT ahmedtahmeed comprehensivecomputationalinvestigationintotheconservedvirulentproteinsofshigellaspeciesunveilspotentialsmallinterferingrnacandidatesasanewtherapeuticstrategyagainstshigellosis