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.