Solid Supported Chemical Syntheses of Both Components of the Lantibiotic Lacticin 3147

Abstract

Lantibiotics are antimicrobial peptides produced by bacteria. Some are employed for food preservation, whereas others have therapeutic potential due to their activity against organisms resistant to current antibiotics. They are ribosomally synthesized and posttranslationally modified by dehydration of serine and threonine residues followed by attack of thiols of cysteines to form monosulfide lanthionine and methyllanthionine rings, respectively. Chemical synthesis of peptide analogues is a powerful method to verify stereochemistry and access structure-activity relationships. However, solid supported synthesis of lantibiotics has been difficult due to problems in generating lanthionines and methyllanthionines with orthogonal protection and good stereochemical control. We report the solid-phase syntheses of both peptides of a two-component lantibiotic, lacticin 3147. Both successive and interlocking ring systems were synthesized on-resin, thereby providing a general methodology for this family of natural products.

Solid-phase peptide synthesis of analogues of the N-terminus A-ring fragment of the lantibiotic nisin: Replacements for the dehydroalanine (Dha) residue at position 5 and the first incorporation of a thioamide residue

“…The resin chosen for SPPS was a 2-chlorotrityl chloride resin (1.33 mmol/g loading) because of its successful use by Vederas for the synthesis of both components of lacticin 3147. 9 The preparation of the analogue containing a glycine in place of Dha5, i.e. Dha5Gly, is exemplified in Scheme 2.…”

“…The other analogues were prepared using similar methodology. Lanthionine 4 was first coupled to the resin to give a reduced loading of 0.16 mmol/g, 9 with the remaining reactive sites being capped with acetic acid. A Kaiser test showed the absence of free NH 2 groups.…”

“…2 However, its stability and solubility decrease considerably at physiological pH which precludes its use as a human therapeutic. The A and B rings of the N-terminus of nisin (nisin [3][4][5][6][7][8][9][10][11][12] ) are critical to its overall biological activity where it binds to the lipid II moiety inhibiting the biosynthesis of the bacterial cell wall. 3 It is known that at physiological pH the two Dha residues at positions 5 and 33 are cleaved by hydrolysis.…”

“…Previously lantibiotics have been prepared by solid-phase peptide synthesis (SPPS), including epilancin X, 8 lacticin 3147a and 3147b, 9 and Cytolysin. 10 These syntheses required the reliable preparation of significant quantities of orthogonally protected lanthionines and -methyllanthionines with tailored protecting groups suitable for SPPS.…”

Lantibiotika‐Kongenere mit nicht‐kanonischen Aminosäuren durch ribosomale In‐vivo‐Peptidsynthese

“…[2] Die Mçglichkeiten zur Vergrçßerung der strukturellen Vielfalt dieser Peptide sind durch die RPS auf die 20 kanonischen Aminosäuren (kAS) begrenzt. Andererseits ist eine Totalsynthese solcher Peptide nur unter Einschränkungen mçglich, [3] wobei semisynthetische Modifikationen mit leicht zugänglichen funktionellen Gruppen selbst mithilfe von zielgerichteter Mutagenese ebenfalls nur in begrenztem Umfang erfolgreich durchführ-bar sind.…”