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•Medium-sized macrocycles can address novel disease-relevant targets.•Protein epitope mimetics (PEM) are mimics β-hairpin and α-helical protein epitopes.•PEM molecules can be ...efficiently synthesized using high-throughput parallel synthesis.•A summary of PEM molecules in clinical development is given.
Fully synthetic medium-sized macrocyclic peptides mimicking the key β-hairpin and α-helical protein epitopes relevant in many protein–protein interactions have emerged as a novel class of drugs with the potential to fill an important gap between small molecules and proteins. Conformationally stabilized macrocyclic scaffolds represent ideal templates for medicinal chemists to incorporate bioactive peptide and protein pharmacophores in order to generate novel drugs to treat diseases with high unmet medical need. This review describes recent approaches to design and generate large libraries of such macrocycles, for hit identification, and for their efficient optimization. Finally, this review describes some of the most advanced protein epitope mimetic (PEM) macrocycles in clinical development.
This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal ...infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed.
•Review article covering recent progress in the field of peptide antibiotics.•Peptide antibiotics with antimicrobial efficacy demonstrated in vivo.•Peptide antibiotics with novel and established modes of action and targets.•Addressed targets are at the outer or inner membrane, or in the cytoplasm.•Targets include LPS transport and outer membrane protein folding.
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Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design ...novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments.
This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features that potentially modulate ...cellular permeability. Examples range from exclusively peptidic structures like cyclosporin A or phepropeptins to compounds with mostly non-peptidic character, such as telomestatin or largazole. Furthermore, semisynthetic approaches and synthesis platforms to generate general and focused libraries of compounds at the interface of cyclic peptides and non-peptidic macrocycles are discussed.
The α-ketoacid-hydroxylamine (KAHA) ligation with 5-oxaproline enables the direct cyclization of peptides upon cleavage from a solid support, without coupling reagents, protecting groups, or ...purification of the linear precursors. This Fmoc SPPS-based method was applied to the synthesis of a library of 24 homoserine-containing cyclic peptides and was compared side-by-side with the synthesis of the same products using a standard method for cyclizing side-chain protected substrates. A detailed mechanistic study including
H and
O labeling experiments and the characterization of reaction intermediates by NMR and mass spectrometry is reported.
The α-ketoacid-hydroxylamine (KAHA) ligation with 5-oxaproline enables the direct cyclization of peptides upon cleavage from a solid support, without coupling reagents, protecting groups, or ...purification of the linear precursors. This Fmoc SPPS-based method was applied to the synthesis of a library of 24 homoserine-containing cyclic peptides and was compared side-by-side with the synthesis of the same products using a standard method for cyclizing side-chain protected substrates. A detailed mechanistic study including
2
H and
18
O labeling experiments and the characterization of reaction intermediates by NMR and mass spectrometry is reported.
The α-ketoacid-hydroxylamine (KAHA) ligation enables the direct cyclization of unprotected peptides upon cleavage, without coupling reagents or purification of precursors. We report the synthesis of a library of 24 cyclic peptides and a detailed mechanistic study.
The α-ketoacid–hydroxylamine (KAHA) ligation enables the direct cyclization of unprotected peptides upon cleavage, without coupling reagents or purification of precursors. We report the synthesis of ...a library of 24 cyclic peptides and a detailed mechanistic study.
The α-ketoacid–hydroxylamine (KAHA) ligation with 5-oxaproline enables the direct cyclization of peptides upon cleavage from a solid support, without coupling reagents, protecting groups, or purification of the linear precursors. This Fmoc SPPS-based method was applied to the synthesis of a library of 24 homoserine-containing cyclic peptides and was compared side-by-side with the synthesis of the same products using a standard method for cyclizing side-chain protected substrates. A detailed mechanistic study including
2
H and
18
O labeling experiments and the characterization of reaction intermediates by NMR and mass spectrometry is reported.
The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills ...Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant
and
strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.
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