Structure-based design of a Plasmodium vivax Duffy-binding protein immunogen focuses the antibody response to functional epitopes.

IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Protein Science Pub Date : 2024-08-01 DOI:10.1002/pro.5095
Thayne H Dickey, Holly McAleese, Nichole D Salinas, Lynn E Lambert, Niraj H Tolia
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引用次数: 0

Abstract

The Duffy-binding protein (DBP) is a promising antigen for a malaria vaccine that would protect against clinical symptoms caused by Plasmodium vivax infection. Region II of DBP (DBP-II) contains the receptor-binding domain that engages host red blood cells, but DBP-II vaccines elicit many non-neutralizing antibodies that bind distal to the receptor-binding surface. Here, we engineered a truncated DBP-II immunogen that focuses the immune response to the receptor-binding surface. This immunogen contains the receptor-binding subdomain S1S2 and lacks the immunodominant subdomain S3. Structure-based computational design of S1S2 identified combinatorial amino acid changes that stabilized the isolated S1S2 without perturbing neutralizing epitopes. This immunogen elicited DBP-II-specific antibodies in immunized mice that were significantly enriched for blocking activity compared to the native DBP-II antigen. This generalizable design process successfully stabilized an integral core fragment of a protein and focused the immune response to desired epitopes to create a promising new antigen for malaria vaccine development.

基于结构设计的间日疟原虫达菲结合蛋白免疫原可将抗体反应集中于功能表位。
达菲结合蛋白(DBP)是一种很有前景的疟疾疫苗抗原,它可以预防间日疟原虫感染引起的临床症状。DBP的II区(DBP-II)包含与宿主红细胞结合的受体结合域,但DBP-II疫苗会引发许多与受体结合表面远端结合的非中和抗体。在这里,我们设计了一种截短的 DBP-II 免疫原,它能将免疫反应集中到受体结合表面。这种免疫原含有受体结合亚域 S1S2,缺乏免疫优势亚域 S3。基于结构的 S1S2 计算设计确定了氨基酸组合变化,这些变化稳定了分离出的 S1S2,而不会扰乱中和表位。与原生 DBP-II 抗原相比,这种免疫原在免疫小鼠体内激发的 DBP-II 特异性抗体的阻断活性显著增强。这种可推广的设计过程成功地稳定了蛋白质的整体核心片段,并将免疫反应集中到了所需的表位上,从而为疟疾疫苗的开发创造了一种前景广阔的新抗原。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Protein Science
Protein Science 生物-生化与分子生物学
CiteScore
12.40
自引率
1.20%
发文量
246
审稿时长
1 months
期刊介绍: Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).
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