RESUMEN
Acinetobacter baumannii is one of the major pathogenic ESKAPE bacterium, which is responsible for about more than 722,000 cases in a year, globally. Despite the alarming increase in multidrug resistance, a safe and effective vaccine for Acinetobacter infections is still not available. Hence in the current study, a multiepitope vaccine construct was developed using linear B cell, cytotoxic T cell, and helper T cell epitopes from the antigenic and well-conserved lipopolysaccharide assembly proteins employing systematic immunoinformatics and structural vaccinology strategies. The multi-peptide vaccine was predicted to be highly antigenic, non-allergenic, non-toxic, and cover maximum population coverage worldwide. Further, the vaccine construct was modeled along with adjuvant and peptide linkers and validated to achieve a high-quality three-dimensional structure which was subsequently utilized for cytokine prediction, disulfide engineering, and docking analyses with Toll-like receptor (TLR4). Ramachandran plot showed 98.3% of the residues were located in the most favorable and permitted regions, thereby corroborating the feasibility of the modeled vaccine construct. Molecular dynamics simulation for a 100 ns timeframe further confirmed the stability of the binding vaccine-receptor complex. Finally, in silico cloning and codon adaptation were also performed with the pET28a (+) plasmid vector to determine the efficiency of expression and translation of the vaccine. Immune simulation studies demonstrated that the vaccine could trigger both B and T cell responses and can elicit strong primary, secondary, and tertiary immune responses. The designed multi-peptide subunit vaccine would certainly expedite the experimental approach for the development of a vaccine against A. baumannii infection.
Asunto(s)
Acinetobacter baumannii , Vacunas de Subunidad , Epítopos de Linfocito T/genética , Adyuvantes Inmunológicos , Adyuvantes FarmacéuticosRESUMEN
COVID-19 is a systemic disease affecting multiple organ systems and caused by infection with the SARS-CoV-2 virus. Two years into the COVID-19 pandemic and after the introduction of several vaccines, the pandemic continues to evolve in part owing to global inequities in access to preventive and therapeutic measures. We are also witnessing the introduction of antivirals against COVID-19. Against this current background, we review the progress made with nanotechnology-based approaches such as nanoformulations to combat the multiorgan effects of SARS-CoV-2 infection from a systems medicine lens. While nanotechnology has previously been widely utilized in the antiviral research domain, it has not yet received the commensurate interest in the case of COVID-19 pandemic response strategies. Notably, SARS-CoV-2 and nanomaterials are similar in size ranging from 50 to 200 nm. Nanomaterials offer the promise to reduce the side effects of antiviral drugs, codeliver multiple drugs while maintaining stability in the biological milieu, and sustain the release of entrapped drug(s) for a predetermined time period, to name but a few conceivable scenarios, wherein nanotechnology can enable and empower preventive medicine and therapeutic innovations against SARS-CoV-2. We conclude the article by underlining that nanotechnology-based interventions warrant further consideration to enable precision planetary health responses against the COVID-19 pandemic.
Asunto(s)
COVID-19 , Pandemias , Antivirales/farmacología , Antivirales/uso terapéutico , Vacunas contra la COVID-19 , Humanos , Nanotecnología , Pandemias/prevención & control , SARS-CoV-2RESUMEN
BACKGROUND: Triple Negative Breast Cancer (TNBC) tends to be more aggressive than other types of breast cancer. Resistance to chemotherapy is a major obstacle hence there is a significant need for new antineoplastic drugs with multi-target potency. Numerous Benzoisoxazole moieties have been found to possess a broad spectrum of pharmacological activities. In the present study, we have synthesized 9 novel derivatives of Benzisoxazole 7(a-i) and screened them for their biological potential. METHODS: Chemical synthesis, Mass spectrometry (HRMS), cell proliferation and cytotoxicity assay, wound healing assay, flow cytometry and nuclear staining. Angio-inhibitory activity assessed by corneal micropocket assay and in vivo peritoneal angiogenesis assay. RESULTS: The Benzisoxazole derivatives 7(a-i) were synthesized and screened for their biological potency by both in vitro and in vivo experimental models. Among the series, compound 3-(1-((3-(3(Benzyloxy)-4-methoxyphenyl)- 4,5-dihydroisoxazole-5-yl)methyl)piperidine-4-yl)6-fluorobenzo[d] isoxazole (7e) was found to be most promising, with an average IC50 value of 50.36 ± 1.7 µM in MTT assay and showed 81.3% cell death. The compound 7e also showed 60-70% inhibition on a recombinant Metastasis-Associated protein (MTA1) induced proliferation and cell migration in MDAMB-231 cells, which is known to play a major role in angiogenesis. The anti-tumour studies inferred the regression of tumour activity. This was due to inhibition of neovascularization and evoking apoptosis process as assessed by corneal vascularization, peritoneal angiogenesis and apoptotic hallmarks in 7e treated cells. CONCLUSION: These findings not only show the biological efficacy of compound 7e but it is also an effective beginning to explore the mechanism of metastasis and cancer therapy strategy targeting MTA1. The observed biological activity makes compound 7e an attractive drug candidate.