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2016 ; 49
(3
): 428-41
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?-AApeptides: Design, Structure, and Applications
#MMPMID26900964
Shi Y
; Teng P
; Sang P
; She F
; Wei L
; Cai J
Acc Chem Res
2016[Mar]; 49
(3
): 428-41
PMID26900964
show ga
The development of sequence-specific peptidomimetics has led to a variety of
fascinating discoveries in chemical biology. Many peptidomimetics can mimic
primary, secondary, and even tertiary structure of peptides and proteins, and
because of their unnatural backbones, they also possess significantly enhanced
resistance to enzymatic hydrolysis, improved bioavailability, and chemodiversity.
It is known that peptide nucleic acids (PNAs) are peptidic sequences developed
for the mimicry of nucleic acids; however, their unique backbone as the molecular
scaffold of peptidomimetics to mimic structure and function of bioactive peptides
has not been investigated systematically. As such, we recently developed a new
class of peptidomimetics, "?-AApeptides", based on the chiral ?-PNA backbone.
They are termed ?-AApeptides because they are the oligomers of
?-substituted-N-acylated-N-aminoethyl amino acids. Similar to other classes of
peptidomimetics, ?-AApeptides are also resistant to proteolytic degradation and
possess the potential to enhance chemodiversity. Moreover, in our scientific
journey on the exploration of this class of peptidomimetics, we have discovered
some intriguing structures and functions of ?-AApeptides. In this Account, we
summarize the current development and application of ?-AApeptides with biological
potential. Briefly, both linear and cyclic (either through head-to-tail or
head-to-side-chain cyclization) ?-AApeptides with diverse functional groups can
be synthesized easily on the solid phase using the synthetic protocol we
developed. ?-AApeptides could mimic the primary structure of peptides, as they
project the same number of side chains as peptides of the same lengths. For
instance, they could mimic the Tat peptide to permeate cell membranes and bind to
HIV RNA with high specificity and affinity. Certain ?-AApeptides show similar
activity to the RGD peptide and target integrin specifically on the cell surface.
?-AApeptides with function akin to fMLF peptides are also identified. More
importantly, we found that ?-AApeptides can fold into discrete secondary
structures, such as helical and ?-turn-like structures. Therefore, they could be
rationally designed for a range of biological applications. For instance,
?-AApeptides can mimic host-defense peptides and display potent and
broad-spectrum activity toward a panel of drug-resistant bacterial pathogens.
Meanwhile, because of their stability against proteolysis and their
chemodiversity, ?-AApeptides are also amenable for combinatorial screening. We
demonstrate that, through combinatorial selection, certain ?-AApeptides are
identified to inhibit A?40 peptide aggregation, suggesting their potential use as
a molecular probe to intervene in Alzheimer's disease. In addition, a few
?-AApeptides identified from the ?-AApeptide library have been shown to bind to
the DNA-binding domain of STAT3 and antagonize STAT3/DNA interactions. Our
studies suggest that, with further studies and exploration on both structures and
functions, ?-AApeptides may emerge to be a new class of peptidomimetics that play
an important role in chemical biology and biomedical sciences.
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