γ-AApeptides as a New Class of Peptidomimetics: Design, Synthesis, and Applications.

Peptidomimetics are studied for medicinal application because of their ability to mimic hierarchical structures of peptides and proteins. To break the limitation and expand the peptidomimetics family, a new class of peptidomimetics based on peptide nucleic acids (PNAs) backbone - "γ-AApeptides" was developed. Compared with previous peptidomimetics, γ-AApeptides possess prominent advantages such as resistance to proteolytic degradation, enhanced chemodiversity, good selectivity and outstanding bioactivity. The synthesis of γ-AApeptides is carried out using a ''monomer building block'' strategy which is facile and efficient. γ-AApeptides are able to mimic primary and secondary structures of therapeutic peptides, which make them promising candidates for molecular probes and potential drug leads. In the past decade, several interesting structures and applications of γ-AApeptides have been developed by different approaches such as structure-based design, combinatorial library screening, and peptides selfassembly and folding. By following the mechanism of host-defense peptides (HDPs), antibiotic γ- AApeptides showed broad-spectrum activity. At the same time, γ-AApeptides can be used for combinatorial library screening because of their structural stability and their chemodiversity. Anticancer agents, anti-T2DM (Type 2 diabetes mellitus) agents, anti-HIV (human immuno-deficiency virus) agents and anti-Alzheimer's disease agents were developed by combinatorial screening and rational design. Furthermore, γ-AApeptides as biopolymers, nanomaterials, supramolecular structures and self-assembly architectures were studied due to their unique backbone structures. Therefore, γ-AApeptides may play an important role in the development of peptidomimetics.

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches.

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.