CONSPECTUS: 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, “γ-AApeptides”, based on the chiral γ-PNA backbone. They are termed γ-AApeptides because they are the oligomers of γ-substituted-N-acylated-N-aminoethyl amino acids. Similar to other classes of peptidomimetics, γ-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 γ-AApeptides. In this Account, we summarize the current development and application of γ-AApeptides with biological potential. Briefly, both linear and cyclic (either through head-to-tail or head-to-side-chain cyclization) γ-AApeptides with diverse functional groups can be synthesized easily on the solid phase using the synthetic protocol we developed. γ-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 γ-AApeptides show similar activity to the RGD peptide and target integrin specifically on the cell surface. γ-AApeptides with function akin to fMLF peptides are also identified. More importantly, we found that γ-AApeptides can fold into discrete secondary structures, such as helical and β-turn-like structures. Therefore, they could be rationally designed for a range of biological applications. For instance, γ-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, γ-AApeptides are also amenable for combinatorial screening. We demonstrate that, through combinatorial selection, certain γ-AApeptides are identified to inhibit Aβ40 peptide aggregation, suggesting their potential use as a molecular probe to intervene in Alzheimer's disease. In addition, a few γ-AApeptides identified from the γ-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, γ-AApeptides may emer...
MicroRNA-106a-5p (MiR-106a-5p), a small non-coding RNA, has been reported to be downregulated in astrocytoma, osteosarcoma and colorectal cancer. However, the expression levels and biological function in renal cell carcinoma (RCC) have not been studied yet. In this study, we found that the miR-106a-5p was significantly downregulated in RCC tissues and cell lines, and that overexpression of miR-106a-5p led to decreased cell metastasis ability in a xenograft model. Inhibition of miR-106a-5p in RCC cell lines altered the cell migration, invasion and wound healing abilities. Mechanistic studies demonstrated that miR-106a-5p directly bound to the 3′-UTR of the PAK5 mRNA and mediated a decrease in the protein expression of PAK5. We further proved that PAK5 protein levels were negatively correlated with the miR-106a-5p expression in both patient samples and xenograft model. In epigenetics, methylation specific PCR experiments indicated that the upstream gene promoter of miR-106a-5p was hypermethylated in RCC, which might be responsible for its downregulation. Our findings suggested that miR-106a-5p might be a potential gene therapy target for the treatment of RCC metastasis.
Angiogenesis, formation of new blood vessels from the existing vascular network, is a hallmark of cancer cells that leads to tumor vascular proliferation and metastasis. This process is mediated through the binding interaction of VEGF-A with VEGF receptors. However, the balance between pro-angiogenic and anti-angiogenic effect after ligand binding yet remains elusive and is therefore challenging to manipulate. To interrogate this interaction, herein we designed a few sulfono-γ-AA peptide based helical peptidomimetics that could effectively mimic a key binding interface on VEGF (helix-α1) for VEGFR recognition. Intriguingly, although both sulfono-γ-AA peptide sequences V2 and V3 bound to VEGF receptors tightly, in vitro angiogenesis assays demonstrated that V3 potently inhibited angiogenesis, whereas V2 activated angiogenesis effectively instead. Our findings suggested that this distinct modulation of angiogenesis might be due to the result of selective binding of V2 to VEGFR-1 and V3 to VEGFR-2, respectively. These molecules thus provide us a key to switch the angiogenic signaling, a biological process that balances the effects of pro-angiogenic and anti-angiogenic factors, where imbalances lead to several diseases including cancer. In addition, both V2 and V3 exhibited remarkable stability toward proteolytic hydrolysis, suggesting that V2 and V3 are promising therapeutic agents for the intervention of disease conditions arising due to angiogenic imbalances and could also be used as novel molecular switching probes to interrogate the mechanism of VEGFR signaling. The findings also further demonstrated the potential of sulfono-γ-AA peptides to mimic the α-helical domain for protein recognition and modulation of protein–protein interactions.
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