A NOVEL B-CELL MULTIEPITOPE SENOVACCINE DESIGNED TO IMPEDE AGE-ASSOCIATED PATHOLOGIES AND PROMOTE HEALTHY AGING

Abstract

Age-associated illnesses are a consequence of accumulating senescent cells within the body. These non-proliferative derivatives of normal cells evade cytotoxic immune clearance and supplement disease pathogenesis and aging. While senescence can be deemed beneficial during embryogenesis to prevent tumour progression, late-onset senescence is the causative agent of many comorbidities like osteoarthritis, atherosclerosis, Alzheimer's disease, Parkinson’s disease, and even cancer. The replacement of functionally viable cells by dormant senescent cells causes an accelerated loss of function and aging in tissues and organs. Recent experimentation shows that the elimination of these agglomerating senescent cells can restore certain functionality to the tissues and improve the health span and quality of survivorship. Two available modes of senotherapies include senomorphics, which alter the morphology and functioning of the senescent cells to imitate those of younger cells or delay the aging, and senolytics which selectively lyse the senescent cells. Since most senolytic drugs show short-lived, off-target effects with high toxicity, a search for a relatively safer and highly specific modality is warranted. A new, pre-emptive form of treatment includes the development of prophylactics that trigger the immune system to target and eliminate the senescent cells, called senovaccines. This study uses the antigens urokinase plasminogen activator receptor (uPAR) and Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB), regarded as characteristic cellular markers of senescent cells, as promising senoantigens to provide an in silico design of a senovaccine. This research presents a novel B-cell multiepitope senovaccine that can potentially elicit a long-lasting humoral immune response. We predicted five highly antigenic peptides and combined them with an v adjuvant beta-defensin using suitable linkers. These linear B-cell epitopes were derived as consensus sequences, fulfilling the criteria of high antigenicity, hydrophilicity, surface accessibility, flexibility, and availability of beta-turns. The senovaccine construct fulfilled the criteria of nonallergenicity, nontoxicity, solubility, and stability. The senovaccine construct had an ideal molecular weight and complexity that would enable the elicitation of an effective humoral immune response. Additional properties of its hydrophilicity and thermal stability attest to the success of this vaccine in future tangible forms as an administered vaccine concoction. The secondary and tertiary structure analysis predicted the success of the senovaccine in dynamic in vivo environments. Molecular docking and molecular simulation analysis revealed that the senovaccine construct can form productive and stable complexes with the variable region of anti uPAR antibody. In silico cloning of the vaccine, construct attests to its ease of expression in suitable hosts. The computationally designed B-cell multiepitope senovaccine provides us with a novel plausible model that can be explored further for the development of efficacious senovaccines that support healthy aging.