Conspectus
The last decades have witnessed
unprecedented scientific breakthroughs
in all the fields of knowledge, from basic sciences to translational
research, resulting in the drastic improvement of the lifespan and
overall quality of life. However, despite these great advances, the
treatment and diagnosis of some diseases remain a challenge. Inspired
by nature, scientists have been exploring biomolecules and their derivatives
as novel therapeutic/diagnostic agents. Among biomolecules, proteins
raise much interest due to their high versatility, biocompatibility,
and biodegradability.
Protein binders (binders) are proteins
that bind other proteins,
in certain cases, inhibiting or modulating their action. Given their
therapeutic potential, binders are emerging as the next generation
of biopharmaceuticals. The most well-known example of binders are
antibodies, and inspired by them researchers have developed alternative
binders using protein design approaches. Protein design can be based
on naturally occurring proteins in which, by means of rational design
or combinatorial approaches, new binding interfaces can be engineered
to obtain specific functions or based on de novo proteins
emerging from state-of-the-art computational methodologies.
Among the novel designed proteins, a class of engineered repeat
proteins, the consensus tetratricopeptide repeat (CTPR) proteins,
stand out due to their stability and robustness. The CTPR unit is
a helix-turn-helix motif constituted of 34 amino acids, of which only
8 are essential to ensure correct folding of the structure. The small
number of conserved residues of CTPR proteins leaves plenty of freedom
for functional mutations, making them a base scaffold that can be
easily and reproducibly tailored to endow desired functions to the
protein. For example, the introduction of metal-binding residues (e.g.,
histidines, cysteines) drives the coordination of metal ions and the
subsequent formation of nanomaterials. Additionally, the CTPR unit
can be conjugated with other peptides/proteins or repeated in tandem
to encode larger CTPR proteins with superhelical structures. These
properties allow for the design of both binder and nanomaterial-coordination
modules as well as their combination within the same molecule, making
the CTPR proteins, as we have demonstrated in several recent examples,
the ideal platform to develop protein–nanomaterial hybrids.
Generally, the fusion of two distinct materials exploits the best
properties of each; however, in protein–nanomaterial hybrids,
the fusion takes on a new dimension as new properties arise.
These hybrids have ushered the use of protein-based nanomaterials
as biopharmaceuticals beyond their original therapeutic scope and
paved the way for their use as theranostic agents. Despite several
reports of protein-stabilized nanomaterials found in the literature,
these systems offer limited control in the synthesis and properties
of the grown nanomaterials, as the protein acts just as a stabilizing
agent with no significant functional contribution. T...