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Living host system possess mechanisms like innate immune system to combat against inflammation, stress singling, and cancer. These mechanisms are initiated by PAMP and DAMP mediated recognition by PRR. PRR is consist of variety of nucleic acid sensors like-RNA sensors. They play crucial role in identifying exogenous and endogenous RNA molecules, which subsequently mediate pro/inflammatory cytokine, IFN and ISGs response in traumatized or tumorigenic conditions. The sensors can sensitize wide range of nucleic acid particle in term of size and structure, while each category sensors belongs subclasses with differentially expressed in cell and distinguished functioning mechanisms. They are also able to make comparison between self and non-self-nucleic acid molecules through specific mechanisms. Besides exhibiting anti-inflammatory and anti-tumorigenic responses, RNA sensors cover the broad spectrum of response mechanisms. Transcriptionally RNA sensors undergo with tight epigenetic regulations. In this review study, we will be going to discuss about the details of RNA sensors, their functional mechanisms and epi-transactional regulations.
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Ácidos Nucleicos , RNA , Epigênese Genética , Humanos , Imunidade Inata/genética , Inflamação , RNA/genéticaRESUMO
BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease transmitted to humans and livestock animals through the bite of infected ticks or close contact with infected persons' blood, organs, or other bodily fluids. The virus is responsible for severe viral hemorrhagic fever outbreaks, with a case fatality rate of up to 40%. Despite having the highest fatality rate of the virus, a suitable treatment option or vaccination has not been developed yet. Therefore, this study aimed to formulate a multiepitope vaccine against CCHF through computational vaccine design approaches. METHODS: The glycoprotein, nucleoprotein, and RNA-dependent RNA polymerase of CCHF were utilized to determine immunodominant T- and B-cell epitopes. Subsequently, an integrative computational vaccinology approach was used to formulate a multi-epitopes vaccine candidate against the virus. RESULTS: After rigorous assessment, a multiepitope vaccine was constructed, which was antigenic, immunogenic, and non-allergenic with desired physicochemical properties. Molecular dynamics (MD) simulations of the vaccine-receptor complex show strong stability of the vaccine candidates to the targeted immune receptor. Additionally, the immune simulation of the vaccine candidates found that the vaccine could trigger real-life-like immune responses upon administration to humans. CONCLUSIONS: Finally, we concluded that the formulated multiepitope vaccine candidates would provide excellent prophylactic properties against CCHF.
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Vírus da Febre Hemorrágica da Crimeia-Congo , Febre Hemorrágica da Crimeia , Vacinas Virais , Humanos , Animais , Febre Hemorrágica da Crimeia/prevenção & controle , Febre Hemorrágica da Crimeia/epidemiologia , Vírus da Febre Hemorrágica da Crimeia-Congo/genética , Surtos de Doenças/prevenção & controle , VacinaçãoRESUMO
Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from Catharanthus roseus and Avicennia marina to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.
Assuntos
Antineoplásicos , Avicennia , Catharanthus , Neoplasias Colorretais , Antineoplásicos/química , Antineoplásicos/farmacologia , Avicennia/metabolismo , Catharanthus/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Timidilato Sintase/metabolismoRESUMO
Epigenetic modifications play an important role in disease pathogenesis and therefore are a focus of intense investigation. Epigenetic changes include DNA, RNA, and histone modifications along with expression of non-coding RNAs. Various factors such as environment, diet, and lifestyle can influence the epigenome. Dietary nutrients like vitamins can regulate both physiological and pathological processes through their direct impact on epigenome. Vitamin A acts as a major regulator of above-mentioned epigenetic mechanisms. B group vitamins including biotin, niacin, and pantothenic acid also participate in modulation of various epigenome. Further, vitamin C has shown to modulate both DNA methylation and histone modifications while few reports have also supported its role in miRNA-mediated pathways. Similarly, vitamin D also influences various epigenetic modifications of both DNA and histone by controlling the regulatory mechanisms. Despite the information that vitamins can modulate the epigenome, the detailed mechanisms of vitamin-mediated epigenetic regulations have not been explored fully and hence further detailed studies are required to decipher their role at epigenome level in both normal and disease pathogenesis. The current review summarizes the available literature on the role of vitamins as epigenetic modifier and highlights the key evidences for developing vitamins as potential epidrugs.
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Vitamina A , Vitaminas , Metilação de DNA , Epigênese Genética , Histonas/metabolismo , Vitaminas/farmacologiaRESUMO
Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, has long been found to be dysregulated in human lung adenocarcinomas (LUADs). Nevertheless, the function, mutational profile, epigenetic regulation, co-expression profile, and clinicopathological significance of the GPC3 gene in LUAD progression are not well understood. In this study, we analyzed cancer microarray datasets from publicly available databases using bioinformatics tools to elucidate the above parameters. We observed significant downregulation of GPC3 in LUAD tissues compared to their normal counterparts, and this downregulation was associated with shorter overall survival (OS) and relapse-free survival (RFS). Nevertheless, no significant differences in the methylation pattern of GPC3 were observed between LUAD and normal tissues, although lower promoter methylation was observed in male patients. GPC3 expression was also found to correlate significantly with infiltration of B cells, CD8+, CD4+, macrophages, neutrophils, and dendritic cells in LUAD. In addition, a total of 11 missense mutations were identified in LUAD patients, and ~1.4% to 2.2% of LUAD patients had copy number amplifications in GPC3. Seventeen genes, mainly involved in dopamine receptor-mediated signaling pathways, were frequently co-expressed with GPC3. We also found 11 TFs and 7 miRNAs interacting with GPC3 and contributing to disease progression. Finally, we identified 3 potential inhibitors of GPC3 in human LUAD, namely heparitin, gemcitabine and arbutin. In conclusion, GPC3 may play an important role in the development of LUAD and could serve as a promising biomarker in LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Masculino , Glipicanas/genética , Glipicanas/metabolismo , Relevância Clínica , Epigênese Genética , Recidiva Local de Neoplasia/genética , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/patologia , PrognósticoRESUMO
Innate immune sensor IFN-induced protein 16 (IFI16) exhibits anti-inflammatory effects via IFNß and IFN-stimulated gene (ISG)15 induction in cancer cells. Epigallocatechin gallate (EGCG) is a potent natural DNA methyltransferase inhibitor (DNMTi). Previous studies revealed that conventional DNMTis, such as 5-azacytidine (5-aza-dc), induce IFI16 expression and EGCG decreases DNMT mRNA expression and global methylation (5mC) level via promoter demethylation of tumor suppressor genes in cancer cell lines. To the best of our knowledge, however, EGCG-mediated IFI16 promoter methylation status has been overlooked. Here, initial screening was performed to determine IFI16 expression and its correlation with DNMTs in cancer cell lines from various databases. Following treatment of breast cancer cell lines with 5-aza-dc, vitamin C and EGCG, expression levels of IFI16 and its downstream transcription targets IFNß1 and ISG15 were assessed using RT-qPCR, and the 5mC level was assessed using ELISA. In silico molecular docking simulation was performed for all DNMTs to predict the mode of ligands binding with proteins. Finally, promoter methylation level in IFI16 gene was assessed following EGCG treatment. EGCG treatment induced IFI16 expression, interacted with certain amino acids residues in DNMT proteins and decreased 5mC level and promoter methylation of IFI16. The present results may provide a basis for targeting IFI16 expression as a therapeutic option in breast cancer cell lines.
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Triple-negative breast cancer (TNBC) is a highly resistant, lethal, and metastatic sub-division of breast carcinoma, characterized by the deficiency of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In women, TNBC shows a higher aggressive behavior with poor patient prognosis and a higher recurrence rate during reproductive age. TNBC is defined by the presence of epithelial- to-mesenchymal-transition (EMT), which shows a significant role in cancer progression. At the epigenetic level, TNBC is characterized by epigenetic signatures, such as DNA methylation, histone remodeling, and a host of miRNA, MiR-193, LncRNA, HIF- 2α, eEF2K, LIN9/NEK2, IMP3, LISCH7/TGF-ß1, GD3s, KLK12, mediated regulation. These modifications either are silenced or activate the necessary genes that are prevalent in TNBC. The review is based on epigenetic mediated mechanistic changes in TNBC. Furthermore, Thymoquinone (TQ), Regorafenib, Fangjihuangqi decoction, Saikosaponin A, and Huaier, etc., are potent antitumor natural compounds extensively reported in the literature. Further, the review emphasizes the role of these natural compounds in TNBC and their possible epigenetic targets, which can be utilized as a potential therapeutic strategy in the treatment of TNBC.
Assuntos
MicroRNAs , Neoplasias de Mama Triplo Negativas , Epigênese Genética , Transição Epitelial-Mesenquimal/genética , Feminino , Histonas/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Quinases Relacionadas a NIMA/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 µM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein.
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Tumor cells detached from the extracellular matrix (ECM) undergo anoikis resistance and metabolic reprogramming to facilitate cancer cell survival and promote metastasis. During ECM detachment, cancer cells utilize genomic methylation to regulate transcriptional events. One-carbon (1C) metabolism is a well-known contributor of SAM, a global substrate for methylation reactions, especially DNA methylation. DNA methylation-mediated repression of NK cell ligands MICA and MICB during ECM detachment has been overlooked. In the current work, we quantitated the impact of ECM detachment on one-carbon metabolites, expression of 1C regulatory pathway genes, and total methylation levels. Our results showed that ECM detachment promotes the accumulation of one-carbon metabolites and induces regulatory pathway genes and total DNA methylation. Furthermore, we measured the expression of well-known targets of DNA methylation in NK cell ligands in cancer cells, namely, MICA/B, during ECM detachment and observed low expression compared to ECM-attached cancer cells. Finally, we treated the ECM-detached cancer cells with vitamin C (a global methylation inhibitor) and observed a reduction in the promoter methylation of NK cell ligands, resulting in MICA/B re-expression. Treatment with vitamin C was also found to reduce global DNA methylation levels in ECM-detached cancer cells.
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The gut microbiota consists of a community of microorganisms that inhabit the large intestine. These microbes play important roles in maintaining gut barrier integrity, inflammation, lipid and carbohydrate metabolism, immunity, and protection against pathogens. However, recent studies have shown that dysfunction in the gut microbiota composition can lead to the development of several diseases. Urolithin A has recently been approved as a functional food ingredient. In this study, we examined the potentials of urolithin A (Uro-A) and B (Uro-B) in improving metabolic functions and their impact on gut microbiota composition under a metabolically unchallenged state in normal rats. Male Wistar rats (n = 18) were randomly segregated into three groups, with Group 1 serving as the control group. Groups 2 and 3 were administered with 2.5 mg/kg Uro-A and Uro-B, respectively, for four weeks. Our results showed that both Uro-A and B improved liver and kidney functions without affecting body weight. Metagenomic analysis revealed that both Uro-A and B induced the growth of Akkermansia. However, Uro-A decreased species diversity and microbial richness and negatively impacted the composition of pathogenic microbes in normal rats. Taken together, this study showed the differential impacts of Uro-A and B on the gut microbiota composition in normal rats and would thus serve as a guide in the choice of these metabolites as a functional food ingredient or prebiotic.
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Cumarínicos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Metagenoma/efeitos dos fármacos , Animais , Ingredientes de Alimentos , Alimento Funcional , Masculino , Ratos , Ratos WistarRESUMO
Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.
Assuntos
Enzima de Conversão de Angiotensina 2/química , Antivirais/química , Produtos Biológicos/química , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/química , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Produtos Biológicos/farmacocinética , Produtos Biológicos/toxicidade , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/metabolismo , Relação Estrutura-AtividadeRESUMO
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a virus that manifests itself in viral infection with fever, cough, shortness of breath, renal failure and severe acute pneumonia, which often result in a fatal outcome. MERS-CoV has been shown to spread between people who are in close contact. Transmission from infected patients to healthcare personnel has also been observed and is irredeemable with present technology. Genetic studies on MERS-CoV have shown that ORF1ab encodes replicase polyproteins and play a foremost role in viral infection. Therefore, ORF1ab replicase polyprotein may be used as a suitable target for disease control. Viral activity can be controlled by RNA interference (RNAi) technology, a leading method for post transcriptional gene silencing in a sequence-specific manner. However, there is a genetic inconsistency in different viral isolates; it is a great challenge to design potential RNAi (miRNA and siRNA) molecules which can silence the respective target genes rather than any other viral gene simultaneously. In the current study, four effective miRNA and five siRNA molecules for silencing of nine different strains of MERS-CoV were rationally designed and corroborated using computational methods, which might lead to knockdown the activity of virus. siRNA and miRNA molecules were predicted against ORF1ab gene of different strains of MERS-CoV as effective candidate using computational methods. Thus, this method may provide an insight for the chemical synthesis of antiviral RNA molecule for the treatment of MERS-CoV, at genomic level.
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Biologia Computacional/métodos , Inativação Gênica , MicroRNAs/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , RNA Interferente Pequeno/metabolismo , Algoritmos , Composição de Bases , Sequência de Bases , MicroRNAs/genética , Conformação de Ácido Nucleico , RNA Interferente Pequeno/genética , TermodinâmicaRESUMO
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a virus that manifests itself in viral infection with fever, cough, shortness of breath, renal failure and severe acute pneumonia, which often result in a fatal outcome. MERS-CoV has been shown to spread between people who are in close contact. Transmission from infected patients to healthcare personnel has also been observed and is irredeemable with present technology. Genetic studies on MERS-CoV have shown that ORF 1ab encodes replicase polyproteins and play a foremost role in viral infection. Therefore, ORF 1ab replicase polyprotein may be used as suitable target for disease control. Viral activity can be controlled by RNA interference (RNAi) technology, a leading method for post transcriptional gene silencing in a sequence specific manner. However, there is a genetic inconsistency in different viral isolates; it is a great challenge to design potential RNAi (miRNA and siRNA) molecules which can silence the respective target genes rather than any other viral gene simultaneously. In current study four effective miRNA and five siRNA molecules for silencing of nine different strains of MERS-CoV were rationally designed and corroborated using computational methods, which might lead to knockdown the activity of virus. siRNA and miRNA molecules were predicted against ORF1ab gene of different strains of MERS-CoV as effective candidate using computational methods. Thus, this method may provide an insight for the chemical synthesis of antiviral RNA molecule for the treatment of MERS-CoV, at genomic level.
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Plague is a major health concern and Yersinia pestis plays the central causal role in this disease. Yersinia pestis has developed resistance against the commonly available drugs. So, it is now a key concern to find a new drug target. Cysteine protease YopT enzyme is an important factor used by Yersinia pestis for pathogenesis in its host and it has the anti-phagocytic function of removal of C-termini lipid modification. The 3D structure of cysteine protease YopT of Yersinia pestis was determined by means of homology modeling through multiple alignments followed by intensive optimization and validation. The modeling was done by Phyre 2 and refined by ModRefiner. The obtained model was verified with structure validation programs such as PROCHECK, verify 3D and ERRAT for reliability. Interacting partners and active sites were also determined. PROCHECK analysis showed that 93% of the residues are in the most favored region, 5.9% are in the additional allowed region and 1.1% are in the generously allowed region of the Ramachandran plot. The verify 3D value of 0.78 indicates that the environmental profile of the model is good. SOPMA is employed for calculation of the secondary structural features of cysteine protease YopT. Active site determination through CASTp proposes that this protein can be utilized as a potential drug target. However, these findings should further be confirmed by wet lab studies for a targeted therapeutic agent design against Yersinia pestis.
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The Middle East respiratory syndrome coronavirus (MERS-CoV) is a virus that manifests itself in viral infection with fever, cough, shortness of breath, renal failure and severe acute pneumonia, which often result in a fatal outcome. MERS-CoV has been shown to spread between people who are in close contact. Transmission from infected patients to healthcare personnel has also been observed and is irredeemable with present technology. Genetic studies on MERS-CoV have shown that ORF 1ab encodes replicase polyproteins and play a foremost role in viral infection. Therefore, ORF 1ab replicase polyprotein may be used as suitable target for disease control. Viral activity can be controlled by RNA interference (RNAi) technology, a leading method for post transcriptional gene silencing in a sequence specific manner. However, there is a genetic inconsistency in different viral isolates; it is a great challenge to design potential RNAi (miRNA and siRNA) molecules which can silence the respective target genes rather than any other viral gene simultaneously. In current study four effective miRNA and five siRNA molecules for silencing of nine different strains of MERS-CoV were rationally designed and corroborated using computational methods, which might lead to knockdown the activity of virus. siRNA and miRNA molecules were predicted against ORF1ab gene of different strains of MERS-CoV as effective candidate using computational methods. Thus, this method may provide an insight for the chemical synthesis of antiviral RNA molecule for the treatment of MERS-CoV, at genomic level.
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BACKGROUND: The herpes simplex virus (HSV-1) is a virus that manifests itself in viral infection with painful, watery blisters in the skin or on the genitals as well as mucous membrane such as the mouth or lips. During an outbreak, the disease is contagious particularly and is irredeemable with present technology. Genetic studies of HSV-1 have shown that ICP22 (US1) gene is an immediate early gene and is responsible for genome replication and also has contribution in viral infection. METHOD: For disease diagnosis, ICP22 (US1) gene may be suitable target. Viral activity can be controlled through RNA interference technology, a significant method for the post-transcriptional gene silencing. However, in different viral isolates there is a genetic variability; it is very challenging to design possible siRNA molecules which can silence the respective target genes. The work was done by using various computational tools as similarity search, target alignment, secondary structure prediction and RNA interaction evaluation. RESULT: In our study two effective siRNA molecules for ICP22 (US1) gene silencing of seven different strains of HSV-1 were rationally designed and authenticated using computational methods, which might lead to knockdown the viral activity. CONCLUSION: siRNA molecules were foreseen against ICP22 (US1) gene of different strains of HSV-1 as effective aspirant using computational methods. Thus, the approach may deliver a vision for the chemical synthesis of antiviral RNA molecule for treatment of HSV-1, at genomic level.