Abstract
Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency.
Highlights
Targeted therapeutics are changing the established medical paradigm
Peptides, which are defined by the FDA as polymers composed of 40 or fewer amino acids [1], lie between small molecules and biotherapeutics and can combine the best of the two worlds
Many linear all-L peptides have been shown to provide efficient targeting, numerous studies prove that enhancing peptide resistance to proteolysis may further boost targeting and cell penetration
Summary
Targeted therapeutics are changing the established medical paradigm. This type of therapeutics is capable of selectively affecting desired cells, thereby dramatically reducing side effects. In order to increase tissue selectivity of nano- and biotherapeutics other than antibodies, many efforts are devoted to exploring more accessible targeting moieties such as small molecules and peptides. Despite the extensive literature describing peptides used as targeting and cell-penetrating moieties, little information is available about how peptide conjugation protects them from protease degradation. The question arises about the extent to which increasing the metabolic resistance of targeting peptides is relevant in conjugated peptides Aiming to answer this question, we critically reviewed the recent literature and selected relevant examples to discuss the influence of peptide resistance to proteases in their targeting or cell penetration capacity. Strategies for enhancing the resistance of peptides to proteases range from protection of N- and C-termini to conjugation, including backbone modification, incorporation of alpha amino acids with non-canonical side chains, and cyclization [5] (Figure 1). Peptides with such modifications can be included within the broad classification of “peptidomimetics” [7]
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