Therapeutic peptides: current applications and future directions

Abstract

Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.

Fig. 1

Top-selling non-insulin peptides worldwide in 2019. Data analysis according to Njardarson’s group

Fig. 2

Peptides versus small molecules and biologics. Comparison of advantages and drawbacks between peptides and small molecules or biologics

Fig. 3

Structure of human insulin and human insulin-derived drugs. Structure of human insulin (left, PDB: 1XDA). Modifications on its residues (B-Chain: B3: Asn, B28: Pro, B29: Lys; A-Chain: A21: Asn) resulted in several short- and long-acting insulin drugs (right, see table)

Fig. 4

Sequences and structures of natural hormones GLP-1 and GnRH and their peptidomimetic drugs. a Liraglutide is a GLP-1 derived peptide drug, modified on 26^th residue (K) of its natural sequence. b Leuprolide and degarelix are modified from the natural sequence of GnRH

Fig. 5

Sequences and structures. Exenatide (a) and lugdunin (b)

Fig. 6

A general process of solid-phase peptide synthesis (SPPS) with Fmoc protected amino acids (Fmoc-AA-OH). Fmoc-SPPS consists a cycle of coupling Fmoc-AA-OH to a solid polymeric resin and deprotection of Fmoc to liberate amino groups. The whole process can be carried out in a sieve reactor till the final peptide is cleaved from the resin

Fig. 7

Strategies of peptide cyclization and stabilization of α-helices, β-sheets, and β-strands. The establishment of intramolecular cross-links can stabilize different secondary structures of peptides. Side chain cross-links between i and i + 4 or/and i + 7 and hydrogen bond surrogate cross-links can stabilize α-helices. Side chain-to-side chain, head-to-tail, and side chain-to-tail cyclization can stabilize turn, loop and β structures (β-sheets and β-strands). The D-Pro-L-Pro scaffold can specifically stabilize antiparallel β-hairpins

Fig. 8

Scheme of genetic code expansion. Genetic code expansion enables the site-specific incorporation of an noncanonical amino acid (shown in green filled circle) into a growing peptide chain by suppressing an unique codon (e.g., amber stop codon)

Fig. 9

PEGylation of therapeutic peptides and proteins via genetic code expansion. Azide or acetyl groups are introduced into therapeutic peptides and proteins by genetic code expansion to allow downstream PEGylation modifications

Fig. 10

Non-canonical amino acids described in this review

Fig. 11

Mechanisms of GLP-1 and GLP-1RA peptide drugs in regulation of T2DM. GLP-1 and GLP-1RA peptide drugs treat T2DM by regulating multiple organs functions, such as reducing gastric emptying and gastric acid secretion, reducing appetite, promoting cardiac glucose utilization, accelerating renal natriuresis and diuresis, minimizing glucose production in the liver and increasing insulin secretion in the pancreas

Fig. 12

Mechanism of natriuretic peptide (NPs) regulation. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) regulate cardiac and vascular homeostasis through binding to their receptors (NPR-A, -B and -C) to reduce sympathetic tone, fibrosis and renin secretion to treat cardiovascular diseases

Fig. 13

The structure and sequence of GLP-2 (PDB: 2L63)

Fig. 14

Application of peptides in tumor therapy. a Screening and identification of peptide candidates from chemically synthesized peptide library and phage library. b Using radiolabeled, dye-labeled, or other designed peptides as probes for tumor diagnosis and imaging. c Application of peptide-conjugated nanomaterials in tumor therapy. d Using peptide vaccine and targeting peptides in tumor immunotherapy and targeted therapy