Biomimetic synthesis and optimization of cyclic peptide antibiotics

  title={Biomimetic synthesis and optimization of cyclic peptide antibiotics},
  author={Rahul M. Kohli and Christopher T Walsh and Michael D. Burkart},
Molecules in nature are often brought to a bioactive conformation by ring formation (macrocyclization). A recurrent theme in the enzymatic synthesis of macrocyclic compounds by non-ribosomal and polyketide synthetases is the tethering of activated linear intermediates through thioester linkages to carrier proteins, in a natural analogy to solid-phase synthesis. A terminal thioesterase domain of the synthetase catalyses release from the tether and cyclization. Here we show that an isolated… 

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

Chemical synthesis combined with peptide cyclization mediated by nonribosomal thioesterase domains enabled the synthesis of glycosylated cyclopeptides, inhibitors of integrin receptors, peptide/polyketide hybrids, lipopeptide antibiotics, and streptogramin B antibiotics.

Enzymology of acyl chain macrocyclization in natural product biosynthesis.

The diversity of macrocyclic structures accessed by enzyme catalyzed cyclization of linear acyl chains as well as their inherent substrate tolerance suggests their potential utility in reprogramming natural product biosynthesis pathways or accessing novel macro cyclic structures.

Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis.

The diverse chain termination strategies of nonribosomal peptide and polyketide assembly lines, the structures and mechanisms of the versatile macrocyclization catalysts, and chemoenzymatic approaches for the development of new therapeutics are the focus of this review.

Enzymatic release and macrolactonization of cryptophycins from a safety-catch solid support.

This model study describes the solid-phase synthesis and on-resin cyclization of three cryptophycin analogues using a chemoenzymatic on- Resin macrocyclization strategy using a robust linker that is stable to most chemical synthesis conditions.

Enzymatic Cyclisation of Peptidomimetics with Incorporated (E)‐Alkene Dipeptide Isosteres

The incorporation of a structural element into the linear peptide precursors of the nonribosomal antibiotics surfactin A and tyrocidine A to test the possibility of subsequent cyclisation by the corresponding peptide cyclases (TE) Srf-TE and Tyc-TE, respectively.

Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants

It is described how a single enzyme can catalyze the cyclization of a range of ribosomally synthesized linear peptides into the corresponding cyclic products of varying ring sizes to provide a means for producing large libraries of cyclic peptides without any sequence bias.

Chemoenzymatic macrocycle synthesis using resorcylic acid lactone thioesterase domains.

It is demonstrated that the thioesterase domains (TEs) responsible for macrocyclization of resorcylic acid lactones are promising catalysts for the chemoenzymatic synthesis of 12- to 18-member ring macrolactones andmacrolactams, and shows these TEs to be the most substrate tolerant polyketide macrocyclizing enzymes known.

Cyclization of Fungal Nonribosomal Peptides by a Terminal Condensation-Like Domain

Evidence of a likely universal macrocyclization strategy employed by fungal NRPSs is provided and extensive biochemical and mutational studies confirmed the essential role of the CT domain in catalyzing cyclization in a thiolation domain-dependent fashion.

Synthesis of peptides and pyrazines from β-amino alcohols through extrusion of H2 catalyzed by ruthenium pincer complexes: ligand-controlled selectivity.

A novel method for peptide synthesis is reported, which involves dehydrogenative coupling of b-amino alcohols with extrusion of H2 catalyzed by complex 1 and environmentally benign and atom-economical reaction proceeds under neutral reaction conditions without the use of toxic reagents, activators, condensing agents, or other additives.

Biosynthetic Strategies for Macrocyclic Peptides

This review highlights the broad spectrum of strategy classes, novel platforms, structure diversity, chemical space, and functionalities of macrocyclic peptides enabled by emerging biosynthetic platforms to achieve bioactivity and for therapeutic purposes.



Peptide cyclization catalysed by the thioesterase domain of tyrocidine synthetase

This specificity profile indicates that the tyrocidine synthetase TE, and by analogy many other TE domains, will be able to cyclize and release a broad range of new substrates and products produced by engineered enzymatic assembly lines.

Generality of peptide cyclization catalyzed by isolated thioesterase domains of nonribosomal peptide synthetases.

Solid-phase synthesis and TE-mediated cyclization of a small pool of linear peptide thioesters are reported, providing evidence for the general utility of TE catalysis as a means to synthesize a wide range of macrocyclic compounds.

Harnessing the biosynthetic code: combinations, permutations, and mutations.

This review considers the promise and challenges inherent in the combinatorial manipulation of PKS and NRPS structure in order to generate entirely "unnatural" products.

Dissociation of Antimicrobial and Hemolytic Activities in Cyclic Peptide Diastereomers by Systematic Alterations in Amphipathicity*

The findings show that a highly amphipathic nature is not desirable in the design of constrained cyclo(VKLKVd-YPLKVKLd-YP) peptides and that an optimum amphipATHicity can be defined by systematic enantiomeric substitutions.

Rational design of peptide antibiotics by targeted replacement of bacterial and fungal domains.

A general approach has been developed for targeted substitution of amino acid-activating domains within the srfA operon, which encodes the protein templates for the synthesis of the lipopeptide antibiotic surfactin in Bacillus subtilis.

A new enzyme superfamily - the phosphopantetheinyl transferases.

Conversion of serine-114 to cysteine-114 and the role of the active site nucleophile in acyl transfer by myristoyl-ACP thioesterase from Vibrio harveyi.

Results provide direct kinetic and chemical evidence that S114 is the site of acylation linked to H241 in the charge relay system and have led to the recognition of a more general consensus motif flanking the nucleophilic serine in thioesterases.

The crystal structure of a hydrated gramicidin S–urea complex

THE cyclic decapeptide antibiotic gramicidin S has the sequenceSince its isolation by Gause and Brazhnikova1, several authors have proposed possible conformations2–10. Of these models, the one that

Why and how are peptide-lipid interactions utilized for self defence?

  • K. Matsuzaki
  • Biology, Chemistry
    Biochemical Society transactions
  • 2001
Animals defend themselves against invading pathogenic micro-organisms by utilizing cationic anti-microbial peptides, which rapidly kill various micro-organisms without exerting toxicity against the