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Antimicrobial resistance to conventional antibiotics and the limited alternatives to combat plant-threatening pathogens are worldwide problems. Antibiotic lipopeptides exert remarkable membrane activity, which usually is not prone to fast resistance formation, and often show organism-type selectivity. Additional modes of action commonly complement the bioactivity profiles of such compounds. The present work describes a multicomponent-based methodology for the synthesis of cyclic polycationic lipopeptides with stabilized helical structures. The protocol comprises an on solid support Ugi-4-component macrocyclization in the presence of a lipidic isocyanide. Circular dichroism was employed to study the influence of both macrocyclization and lipidation on the amphiphilic helical structure in water and micellar media. First bioactivity studies against model phytopathogens demonstrated a positive effect of the lipidation on the antimicrobial activity.
Publikation
Conjugate vaccines against encapsulated pathogens like Streptococcus pneumoniae face many challenges, including the existence of multiple serotypes with a diverse global distribution that constantly requires new formulations and higher coverage. Multivalency is usually achieved by combining capsular polysaccharide–protein conjugates from invasive serotypes, and for S. pneumoniae, this has evolved from 7- up to 20-valent vaccines. These glycoconjugate formulations often contain high concentrations of carrier proteins, which may negatively affect glycoconjugate immune response. This work broadens the scope of an efficient multicomponent strategy, leading to multivalent pneumococcal glycoconjugates assembled in a single synthetic operation. The bioconjugation method, based on the Ugi four-component reaction, enables the one-pot incorporation of two different polysaccharide antigens to a tetanus toxoid carrier, thus representing the fastest approach to achieve multivalency. The reported glycoconjugates incorporate three combinations of capsular polysaccharides 1, 6B, 14, and 18C from S. pneumoniae. The glycoconjugates were able to elicit functional specific antibodies against pneumococcal strains comparable to those shown by mixtures of the two monovalent glycoconjugates.
Publikation
The property of the isonitrile group to enable the simultaneous α-addition of a strong electrophile and a nucleophile has always attracted the attention of organic chemists. Its versatility is augmented when recognizing that its high structural compactness, the inertia to most of the naturally occurring functional groups, and relatively prolonged physiological and metabolical stability, convert it into the smallest bioorthogonal group. The discovery and optimization of the isonitrile-tetrazine [4+1] cycloaddition as an alternative tool for the development of ligation and decaging strategies and the recently reported reaction of isonitriles with chlorooximes bring new opportunities for the utilization of this functional group in biological systems. Although several approaches have been reported for the synthesis of isonitrile-modified carbohydrates and polysaccharides, its incorporation in proteins has been barely explored. Besides compiling the reported methods for the assembly of isonitrile-modified proteins, this Mini-Review aims at calling attention to the real potential of this modification for protein ligation, decaging, immobilization, imaging, and many other applications at a low structural and functional cost.