Harnessing Nanobodies for Precision Targeting of Proteoforms: Opportunities and Challenges in Therapeutics and Diagnostics

IF 3.8 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Biology Pub Date : 2025-07-24 DOI:10.1021/acschembio.5c00329

Elise M. Van Fossen, Oscar Rodriguez, Madelyn Berger, Rowan Wooldridge, Leo Gorham, Abdullah Shouaib, Amy C. Sims, John T. Melchior* and Samantha M. Powell*,

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Abstract

Proteoforms are biologically distinct yet structurally similar proteins that play key roles in driving disease progression but are rarely accounted for in the development of therapeutics and diagnostics. Nanobodies (Nbs) have emerged as a therapeutic and diagnostic “silver bullet” as they possess unique structural and functional attributes that offer advantages over traditional antibodies. One of the most profound advantages of Nbs is the heightened sensitivity and ability to distinguish subtle changes in the conformation of a given protein. Thus, Nbs have significant potential as therapeutic and diagnostic agents that can identify and distinguish specific pathological proteoforms that underlie a given disease. However, there remain significant challenges in obtaining sufficient quantities and purities of specific proteoform antigens that are required for engineering proteoform-specific Nbs. Recent advancements in chemical biology tools for precision proteoform synthesis have made this task feasible for the first time. In this perspective, we discuss the advantages and challenges associated with developing proteoform-specific Nbs and how success in this endeavor will significantly advance the fields of therapeutics and diagnostics.

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利用纳米体精确靶向蛋白质形态：治疗和诊断中的机遇和挑战。

蛋白质形态是生物学上不同但结构相似的蛋白质，在驱动疾病进展中起关键作用，但在治疗和诊断的发展中很少被考虑。纳米抗体（Nbs）具有独特的结构和功能属性，与传统抗体相比具有优势，因此已成为治疗和诊断的“银弹”。Nbs最深刻的优点之一是高度的敏感性和区分特定蛋白质构象的细微变化的能力。因此，Nbs具有作为治疗和诊断试剂的巨大潜力，可以识别和区分特定疾病背后的特定病理蛋白质形态。然而，在获得足够数量和纯度的特异性蛋白抗原（用于工程蛋白特异性Nbs）方面仍然存在重大挑战。最近化学生物学工具的进步使得精确的蛋白质合成首次成为可能。从这个角度来看，我们讨论了与开发蛋白质形态特异性Nbs相关的优势和挑战，以及这一努力的成功将如何显著推进治疗学和诊断领域。

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

ACS Chemical Biology 生物-生化与分子生物学

CiteScore

7.50

自引率

5.00%

发文量

353

审稿时长

3.3 months

期刊介绍： ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.