Expanded genetic code for the engineering of ribosomally synthetized and post-translationally modified peptide natural products (RiPPs)

The number of constituent amino acids in ribosomally synthetized and post-translationally modified peptide natural products (RiPPs) is restricted to the 20 canonical amino acids. Microorganisms with an engineered genetic code are capable of delivering the biological, chemical, or physical properties of many unnatural or synthetic noncanonical amino acids, ncAAs (in different combinations of their numbers and chemistry) precisely defined by the chemist at the bench. In this way, post-translational modifications (PTMs) which make RiPPs chemically extremely rich can be augmented by the co-translational insertion of ncAAs. This will dramatically expand the chemical and functional space of these molecules and enable the design of novel and unique sequence combinations with improved specificity, stability, membrane permeability and even better oral availability.

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► RiPPs have high capabilities of target interaction far beyond the field of anti-infectives.
► RiPPs are especially suitable for design and engineering with the genetic code expansion.
► First published studies yielded RiPPs with unnatural/synthetic amino acids.
► Achievement: expanded scope of the in vivo (mainly bacterial) RiPPs synthesis.
► Perspective: design of RiPPS with novel chemistries and unique sequence combinations.