Towards Intracellular Delivery of Peptides

Abstract

In view of our more comprehensive understanding with respect to intracellular pathways and their regulation, a vast number of interesting drug targets appear to be in a space that can be addressed neither by small molecules nor by biologics. Especially, interference with intracellular protein-protein interactions, if successful, seems to offer considerable opportunities to expand the application of peptides as therapeutics, in particular in the field of oncology. This review focuses on requirements for the development of peptide therapeutics aiming at intracellular targets. In addition, an outlook for developments in this field based on recent examples for peptides active in cellular assays, highlighting key requirement to assess permeability, is provided.

Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides

“…In principle, this know-how can then be systematically applied to design permeable and potent macromolecules in an iterative fashion, and should encourage a straight forward development of orally bioavailable peptide therapeutics. Especially, the promotion of permeability while maintaining a good solubility remains a significant challenge and is of interest in our investigation (Marzinzik and Vorherr 2013 ; Vorherr 2015 ; Kwon and Kodadek 2007 ). This intense effort on macromolecules has become extremely important, since for many attractive drug targets no high affinity and selective small molecules complying with the “rule-of-five” (Krämer et al 2016 ; Whitty et al 2016 ) can be identified.…”

Important Considerations Related to Permeability of Peptides

“…Following in vitro profiling, the beneficial effects of the 2-Pal residue with respect to solubility and permeability were clearly demonstrated. In addition, 1 H-NMR in chloroform showed the presence of an H-bond from the pyridyl nitrogen to the backbone. analysis, information related to intracellular localization, target binding and target upregulation is generated.…”

“…Publications relevant for the first topic including cell-penetrating peptides (CPPs), their conjugates, and antimicrobial peptides (AMPs) have been summarized previously. [1] Meanwhile, more recent reviews on CPPs are available and various mechanisms for cellular uptake were discussed in the context of drug discovery. [2,3] Thus, the focus with respect to intracellular delivery is on our detailed study of two stapled peptides and on assay development to enable quantification of intracellular delivery.…”

Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products

“…While recent progress has been made in unraveling structure–permeability relationships in large macrocycles, especially in cyclic peptides, ,− ,− the extent to which these discoveries can be generalized to macrocycles containing non-α-amino acids remains largely unaddressed.…”