RESUMEN
Vaccines have significantly reduced the impact of numerous deadly viral infections. However, there is an increasing need to expedite vaccine development in light of the recurrent pandemics and epidemics. Also, identifying vaccines against certain viruses is challenging due to various factors, notably the inability to culture certain viruses in cell cultures and the wide-ranging diversity of MHC profiles in humans. Fortunately, reverse vaccinology (RV) efficiently overcomes these limitations and has simplified the identification of epitopes from antigenic proteins across the entire proteome, streamlining the vaccine development process. Furthermore, it enables the creation of multiepitope vaccines that can effectively account for the variations in MHC profiles within the human population. The RV approach offers numerous advantages in developing precise and effective vaccines against viral pathogens, including extensive proteome coverage, accurate epitope identification, cross-protection capabilities, and MHC compatibility. With the introduction of RV, there is a growing emphasis among researchers on creating multiepitope-based vaccines aiming to stimulate the host's immune responses against multiple serotypes, as opposed to single-component monovalent alternatives. Regardless of how promising the RV-based vaccine candidates may appear, they must undergo experimental validation to probe their protection efficacy for real-world applications. The time, effort, and resources allocated to the laborious epitope identification process can now be redirected toward validating vaccine candidates identified through the RV approach. However, to overcome failures in the RV-based approach, efforts must be made to incorporate immunological principles and consider targeting the epitope regions involved in disease pathogenesis, immune responses, and neutralizing antibody maturation. Integrating multi-omics and incorporating artificial intelligence and machine learning-based tools and techniques in RV would increase the chances of developing an effective vaccine. This review thoroughly explains the RV approach, ideal RV-based vaccine construct components, RV-based vaccines designed to combat viral pathogens, its challenges, and future perspectives.
Asunto(s)
Inteligencia Artificial , Vacunas , Humanos , Proteoma , Vacunología/métodos , Epítopos , Biología Computacional/métodos , Vacunas de Subunidad , Epítopos de Linfocito T , Simulación del Acoplamiento Molecular , Epítopos de Linfocito BRESUMEN
Alzheimer's disease (AD) is a multifactorial disorder where amyloid beta (Aß) plaques, Ca2+ dysregulation, excessive oxidative stress, mitochondrial dysfunction and synaptic loss operate synergistically to bring about cholinergic deficits and dementia. New therapeutic interventions are gaining prominence as the morbidity and mortality of AD increases exponentially every year. Treating AD with antihypertensive drugs is thought to be a promising intervention; however, its mechanism of action of ameliorating AD needs further investigation. In this context, the present study explores the protective effect of verapamil, an antihypertensive agent of Ca2+ channel blocker (CCB) class against scopolamine-induced in vitro neurotoxicity and in vivo cognitive impairment. Supplementation of verapamil was found to attenuate oxidative stress by preventing mitochondrial injury, and augment the expression of genes involved in the cholinergic function (mACR1), synaptic plasticity (GAP43, SYP) and Ca2+-dependent memory-related genes (CREB1, CREBBP, BDNF). Further, verapamil treatment in mice attenuated the cognitive and behavioural deficits induced by scopolamine as measured by the elevated plus maze and passive avoidance test (P < 0.05). Thus, the present study demonstrates the neuroprotective effect of verapamil against the pathogenesis of AD such as oxidative stress, mitochondrial dysfunction and cognitive decline. These observations emphasize the importance of ?Ca2+ dysregulation' and ?mitochondrial dysfunction' theories in AD and recommends the supplementation of compounds that regulate Ca2+ homeostasis and mitochondrial function in susceptible AD individuals.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Verapamilo/uso terapéutico , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Fármacos Neuroprotectores/farmacología , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Escopolamina , Verapamilo/farmacologíaRESUMEN
The peripheral anionic site (PAS) of acetylcholinesterase (AChE) is involved in amyloid beta (Aß) peptides aggregation of Alzheimer's disease (AD). AChE exhibits an aryl acylamidase (AAA) activity along with the well known esterase activity. Numerous studies have reported the beneficiary effect of metal chelators in AD treatment. Hence, a comparative study on the effect of metal chelators on both the esterase and AAA activity of AChE globular (G4 and G1) molecular forms was performed. The inhibitory effect of 1,10-phenanthroline was high towards AChE esterase activity. The corresponding IC50 values for esterase activity of G4 and G1-form was 190 µM and 770 µM and for AAA activity it was 270 µM and 2.74 mM, respectively. Kinetic studies on both forms of AChE show that 1,10-phenanthroline inhibits esterase in competitive and AAA activity in non-competitive manner. Protection studies further revealed that the nature of 1,10-phenanthroline inhibition on AChE is through its direct binding to protein rather than its metal chelation property. Molecular docking studies shows orientation of 1,10-phenathroline in the PAS through hydrophobic interactions with the PAS residues (Trp286, Tyr124 and Tyr341) and hydrogen bonding with Phe295. Further molecular dynamics simulation of "hAChE-1,10-phenanthroline" complex revealed that both hydrogen and hydrophobic interaction contribute equally for 1,10-phenanthroline binding to hAChE. Such an interaction of 1,10-phenanthroline on PAS may hinder "AChE-Aß peptide" complex formation. Hence, 1,10-phenanthroline can act as a lead molecule for developing drug(s) against AD ailment with dual functions namely, anti-cholinesterase and anti-amyloid aggregation potency in a single chemical entity.