4 DISCUSSION
Antibody mimetics is a research heated topic at a rapid development stage witnessed by bibliometrics analysis, and it is predicted that this trend will continue in the following years. Although the first article retrieved from the Web of Science appeared at the year of 1986 according to the keywords, the first ever research “A synthetic peptide mimotope of the hepatitis C virus NS3 protein induces HCV-reactive antibodies and cytokine-secreting T cells in mice” using molecules that mimic the function of antibody was in 1995 (Wilson et al., 2001 ). The year of 2005 was a landmark moment in the development of antibody mimetics, indicating the transition of methodology and basic research into application stage (Figs. 1, 2). Antibody mimetics is applied into more fields such as neuroscience and contamination monitoring in recent years (Fig. 2). The technical focus of the application of antibody mimetics has shifted from basic biological problems such as protein structure prediction and molecular interaction into some physically and chemically based technology such as nanoparticles and quantum technology (Figs. 2, 4). The combination of these newly developed techniques widens the fields of applications by providing antibody mimetics with more desirable properties at various conditions. Therefore, it is predicted that the development of antibody mimetics will be highly influenced by other technologies. Researchers with interdisciplinary backgrounds may be greatly promote the combinations of new technologies into antibody mimetics.
In antibody engineering, a series of antibody features have been highlighted and pursued, which are all demonstrated by the high frequency of related terms retrieved, for example, high affinity (704), high stability (364), high specificity (110), high penetration, good host mediation, simple preparation, high repeatability, and low cost in mass production, in which affinity is the highly emphasized (Fig. 2).
The challenges encountered in establishing appropriate keywords for the bibliometric analysis stem primarily from inherent limitations in the field. Specifically, the inclusion of all articles, reviews, and book chapters related to antibody mimetics proved challenging due to variations in terminology and categorization. Some authors focused on specific aspects of engineered proteins without explicitly labeling them as antibody mimetics. In addition, the broad nature of the keywords employed in the analysis, as highlighted by the editor, may have resulted in the inclusion of irrelevant papers. To avoid of this issue as much as possible, we conducted comprehensive artificial screening process to refine and confine the selection of the papers for analysis. Moreover, it is important to note that the term “antibody mimetics” is not uniformly adopted as a standardized terminology within this research field. Researchers often interpret protein engineering techniques from different perspectives, leading to the usage of diverse terms such as “synthetic antibody”, “engineered antibody”, and “designed drug molecules”. Concepts and terminologies in this field are various mainly due to the dynamic and expending understanding on antibody molecules, and novel antibody formats designed, as well as the continuous invention, combination, and modification of different technologies in antibody generation from molecular design to mass manufacturing. For instance, only within the last 20 years, the advent of synthetic diversity libraries provides a ‘chemical solution’ to the biological constraints on natural repertoire diversity (Šácha et al., 2016 ). Synthetic approaches are particularly attractive to those seeking to understand the fundamentals of antibody–antigen interactions or to engineer desired antibody properties, as they enable precise control over the composition of diversity incorporated into antigen-binding sites (Miersch & Sidhu, 2012 ). This explains why “synthetic antibody” has been used as a general term referring to part of antibody mimetics (Fig. 5). At the same time, with the increase of application scenarios and the diversification of molecular types of the referenced parent structures, the scope of these terms has also taken on a broader meaning. The molecular structures of antibody mimetics generally include peptides and proteins, while aptamer is an exception, it is a short oligonucleotide sequence (DNA or RNA), which can specifically bind to its target on proteins and other molecules, or the entire cells, for further therapeutic or diagnostic interventions (Yan et al., 2021 ). Meanwhile, it is worth noting that the functional repertoire of antibody mimetics has significantly expanded beyond their traditional role as antigen binders. They have evolved into versatile tools capable of recognizing and binding specific targets for the purpose of detecting analytes in biological samples (Šácha et al., 2016 ;Šubr et al., 2021 ;Yu et al., 2017 ), as well as in separation methods (Olson et al., 2012 ), cancer therapy (Guillard et al., 2017 ; Park et al., 2000 ), targeted drug delivery (Balmforth et al., 2021 ), and in vivo imaging (Chomet et al., 2021 ;Dietrich et al., 2021 ). This diversification of functionality showcases the adaptability and potential applications of antibody mimetics in various research fields. Peptide antibody mimetics is a subset of peptidomimetics which provide alternatives to natural biopolymers (Fig. 5). Both antibody mimetics and peptidomimetics are designed to mimic the structure and/or function of antibodies or peptides, respectively. However, there are several differences between them. Antibody mimetics is typically larger in size and more complex in structure than peptidomimetics, as they often incorporate multiple binding domains and/or structural motifs. Peptidomimetics, on the other hand, are usually smaller and simpler in structure, consisting of one or a few modified amino acids. Antibody mimetics is designed to recognize and bind to specific targets, such as proteins or cells, with high affinity and specificity. The development of computational modeling and structure-based design methods, such as conformational constraint and incorporation of non-natural amino acids, has facilitated the rational design and optimization of peptidomimetics, allowing the peptidomimetics to achieve binding specificity on par with antibodies. In addition, given that peptidomimetics offer advantages such as smaller size, easier synthesis, and better stability compared to antibodies. These attributes make them attractive candidates for drug development, where they can target challenging protein-protein interactions or intracellular targets that are not easily accessible to antibodies. Antibody mimetics can have various modes of action, such as blocking protein-protein interactions (Fernandes et al., 2022 ), inhibiting enzymatic activity (Khalili et al., 2016 ), or inducing cell signaling (Shan et al., 2020 ). Peptidomimetics, on the other hand, typically act as ligands or modulators of specific receptors or signaling pathways (Goodman et al., 2007 ). Throughout the development, researchers from different discipline backgrounds and perspectives have been involved, chemists focusing on the design of chemical conjugates for drug delivery may not interpret these structures as antibody mimetics, as this terminology was arisen from immunology research.