Solid-Phase Synthesis of γ-AApeptides Using a Submonomeric Approach

Wu, Haifan; Amin, Mohamad Nassir; Niu, Youhong; Qiao, Qiao; Harfouch, Nassier; Nimer, Abdelfattah; Cai, Jianfeng

doi:10.1021/ol301406a

Cited by 20 publications

(30 citation statements)

References 37 publications

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“…19,20 The N -alloc γ-AApeptide building blocks are stable and could be prepared in large batches and used for a long period of time. They can be obtained by either Route 1 or Route 2 according to different R groups (Scheme 1b).…”

Section: Synthesis Of γ-Aapeptidesmentioning

confidence: 99%

γ-AApeptides: Design, Structure, and Applications

et al. 2016

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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...

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Section: Synthesis Of γ-Aapeptidesmentioning

confidence: 99%

γ-AApeptides: Design, Structure, and Applications

et al. 2016

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“…Recent developments in peptidomimetics that are formed through insertion into the amino acid backbone or heteroatom replacement indicate that several peptidomimetics form structural designs such as helices, sheets, turns, and loops via noncovalent interactions. To prepare AApeptides, the current literature indicates that different approaches have been developed 32,43. Originally, the synthesis of these peptides was achieved using the building block strategy (Figure 3).…”

Section: Molecular Design and Antibiotic Activity Of Antimicrobial Pementioning

confidence: 99%

Peptidomimetics as a new generation of antimicrobial agents: current progress

Méndez-Samperio¹

2014

IDR

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Antibiotic resistance is an increasing public health concern around the world. Rapid increase in the emergence of multidrug-resistant bacteria has been the target of extensive research efforts to develop a novel class of antibiotics. Antimicrobial peptides (AMPs) are small cationic amphiphilic peptides, which play an important role in the defense against bacterial infections through disruption of their membranes. They have been regarded as a potential source of future antibiotics, owing to a remarkable set of advantageous properties such as broad-spectrum activity, and they do not readily induce drug-resistance. However, AMPs have some intrinsic drawbacks, such as susceptibility to enzymatic degradation, toxicity, and high production cost. Currently, a new class of AMPs termed “peptidomimetics” have been developed, which can mimic the bactericidal mechanism of AMPs, while being stable to enzymatic degradation and displaying potent activity against multidrug-resistant bacteria. This review will focus on current findings of antimicrobial peptidomimetics. The potential future directions in the development of more potent analogs of peptidomimetics as a new generation of antimicrobial agents are also presented.

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“…[9c, 10, 16] In brief, α-AApeptides 1 and 2 were obtained by incorporating the α-AApeptide building block directly in the synthesis. [9a] γ-AApeptides 3–7 were synthesized by using alloc protected γ-AApeptide building blocks.…”

Section: Resultsmentioning

confidence: 99%

“…Half of the side chains in an AApeptide are derived from amino acids, and the other half of side chains come from any acylating agents including carboxylic acids, [10] acyl chlorides, [11] and sulfonyl chlorides [10] . As such, the potential for the introduction of chemically diverse functional groups into AApeptides is limitless.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Characterization of fMLF‐Mimicking AApeptides

Cheng

et al. 2014

ChemBioChem

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The tripeptide N-formyl-Met-Leu-Phe (fMLF) is a potent neutrophil chemoattractant and the reference agonist of the G protein-coupled N-formylpeptide receptor (FPR). As it plays a very important role in host defense and inflammation, there has been considerable interest in the development of fMLF analogues in the hope of identifying potential therapeutic agents. Herein we report the design, synthesis and evaluation of AApeptides that mimic the structure and function of fMLF. The lead AApeptides can effectively induce calcium mobilization and mitogen-activated protein kinase (MAPK) signal transduction pathways in FPR-transfected rat basophilic leukemic (RBL) cells. More intriguingly, at high concentrations, certain AApeptides are even more effective than fMLF in the induction of calcium mobilization. Their agonistic activity is further supported by their ability to stimulate chemotaxis and production of superoxide in HL-60 cells. Similar to fMLF, these AApeptides are much more selective towards FPR1 than FPR2. These results suggest that the fMLF-mimicking AApeptides may emerge to be a new class of therapeutic agents that target FPRs.

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Solid-Phase Synthesis of γ-AApeptides Using a Submonomeric Approach

Cited by 20 publications

References 37 publications

γ-AApeptides: Design, Structure, and Applications

γ-AApeptides: Design, Structure, and Applications

Peptidomimetics as a new generation of antimicrobial agents: current progress

Design, Synthesis and Characterization of fMLF‐Mimicking AApeptides

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