Precision vaccine design targeting the prefusion state of viral glycoproteins: advances in structural vaccinology

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-09-17 DOI:10.1016/j.bcp.2025.117349

Reetesh Kumar , Somnath Maji , Savitri Tiwari , Jyotsna Misra , Jyoti Gupta , Naveen Kumar , Rohan Gupta , Niraj Kumar Jha

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Abstract

The prefusion conformation of viral glycoproteins is a key target for vaccine development because it can induce strong neutralizing antibody responses. Nevertheless, these structures are frequently metastable and susceptible to conformational alterations that diminish immunogenic efficacy. Progress in structural vaccinology has facilitated the meticulous design of viral proteins to maintain their prefusion conformation, thus improving vaccination effectiveness. This study emphasizes essential methodologies in precision vaccine design focused on preserving the structural integrity, solubility, and immunogenicity of viral glycoproteins. Methods include cavity-filling mutations, proline insertions, and disulfide bond engineering have demonstrated efficacy in enhancing structural stiffness and inhibiting unwanted post-fusion rearrangements. Hydrophobic surface residues are frequently substituted with polar or charged residues to boost solubility and minimize aggregation, while the development of salt bridges and helix-stabilizing substitutions further augment heat stability. The removal of proteolytic cleavage sites and the enhancement of hydrophobic core packing facilitate sustained conformational integrity. Alterations to the fusion peptide, an essential conserved area for viral entry, can inhibit early conformational changes, whereas charge-balancing alterations mitigate electrostatic stress. Glycan shielding conceals non-neutralizing or immunodominant epitopes, steering immune reactions towards conserved, protective areas. Collectively, these structure-guided interventions constitute a thorough molecular toolset, facilitating the creation of prefusion-stabilized immunogens for advanced vaccines. Successfully implemented in vaccine candidates for Respiratory Syncytial Virus (RSV), Human Immunodeficiency Virus (HIV), and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), these methodologies establish a solid basis for the swift and logical generation of vaccines against emerging viral threats.

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针对病毒糖蛋白融合前状态的精确疫苗设计：结构疫苗学的进展。

病毒糖蛋白的预融合构象是疫苗开发的关键靶点，因为它可以诱导强烈的中和抗体反应。然而，这些结构经常是亚稳的，易受构象改变的影响，从而降低免疫原性的功效。结构疫苗学的进步促进了病毒蛋白的精细设计，以保持其预融合构象，从而提高了疫苗接种的有效性。本研究强调了精确疫苗设计的基本方法，重点是保持病毒糖蛋白的结构完整性、溶解度和免疫原性。包括空腔填充突变、脯氨酸插入和二硫键工程在内的方法已经证明了增强结构刚度和抑制不需要的融合后重排的有效性。疏水表面残基经常被极性或带电残基取代，以提高溶解度和减少聚集，而盐桥和螺旋稳定取代的发展进一步增强了热稳定性。蛋白水解裂解位点的去除和疏水核心填料的增强促进了持续的构象完整性。融合肽是病毒进入的一个重要的保守区域，它的改变可以抑制早期的构象变化，而电荷平衡的改变则可以减轻静电应力。聚糖屏蔽隐藏非中和或免疫显性表位，将免疫反应转向保守的保护性区域。总的来说，这些结构导向的干预措施构成了一个完整的分子工具集，促进了为高级疫苗创造预灌注稳定的免疫原。这些方法已成功应用于呼吸道合胞病毒（RSV）、人类免疫缺陷病毒（HIV）和严重急性呼吸综合征冠状病毒-2 （SARS-CoV-2）候选疫苗中，为快速、合理地生产针对新出现的病毒威胁的疫苗奠定了坚实的基础。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.