Compounds comprising stapled or stitched peptides for improved drug delivery

Abstract

The invention relates to improvements in drug delivery and to the use of Cell Penetrating Agents (CPA's) or Cell Penetrating Peptides (CPP's) which have been stabilized by, for example: i) stapling two amino acids to form Stapled CPP's (StaP's) or ii) stitching three or more amino acids to form stitched CPP's (StiP's). More particularly there is provided a drug carrying cell penetrating molecule (DCCPM) comprising: a biologically active compound (BAC), and a cell penetrating agent (CPA), which BAC and CPA are linked directly or via a bi-functional linker (BFL). The CPA is a stabilized peptide(CPP) which has a conformation imposed upon it by stapling to form a stapled peptide (StaP) or stitching to form a stitched peptide (StiP). The StiP or StaP comprise a cross link or bridge between atleast two amino acids of the peptide and the cross link or bridge provides a cyclisation between at least two amino acids which are not formed by an olefin metathesis. Cyclisation may be achieved by one or more of: condensation of an aldehyde or ketone with a hydrazine or protected hydrazine; a thiol-ene Michael addition; a di-sulfide formation; a Huisgen 1, 3 di-polar cycloaddition; a reaction between an amine and carboxylic acid; a singlet or triplet based carbine reaction; or a Suzuki or Sonogashira coupling.

Description

[0001] The present invention relates to improvements in drug delivery. [0002] More particularly, the present invention relates to the use of cell penetrating agents (CPAs), and more particularly also to the use of cell penetrating peptides (CPPs) which have been stabilized, for example, by: i) stapling two amino acids to form a staple A spliced ​​CPP (StaP) or ii) three or more amino acids are spliced ​​to form a spliced ​​CPP (StiP). [0003] The present invention differs from the applicant's earlier patent application PCT / GB2016 / 054028 in that a different chemical reaction than olefin metathesis is used to stabilize peptides. These chemical reactions provide for cross-linking or bridging between at least two amino acids of the peptide, and the cross-linking or bridging provides for cyclization between the at least two amino acids. In these alternative chemistries, cyclization is achieved by one or more of the following: [0004] i. Condensation of aldehydes or ketones with...

AI Technical Summary

Problems solved by technology

In addition, the structure will be unstable after systemic administration since reduction of the thiol bond releases the bridge

Also, WO 2016 / 187425 only discloses arginine-rich peptides, so there are still considerable membrane toxicity issues for this technology

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