New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology

Abstract

Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity, the stability and efficacy of peptide analogues currently employed as anticancer drugs or as molecular imaging tracers. The stability of somatostatin, integrins and bombesin analogues in the human body have been significantly increased by cyclization and/or insertion of non-natural amino acids in the peptide sequences. Moreover, the overall pharmacokinetic properties of such analogues and others (including cholecystokinin, vasoactive intestinal peptide and neurotensin analogues) have been improved by PEGylation and glycosylation. Furthermore, conjugation of those peptide analogues to new linkers and bifunctional chelators (such as AAZTA, TETA, TRAP, NOPO etc.), produced radiolabeled moieties with increased half life and higher binding affinity to the cognate receptors. This review describes the most important and recent chemical modifications introduced in the amino acid sequences as well as linkers and new bifunctional chelators which have significantly improved the specificity and sensitivity of peptides used in oncologic diagnosis and therapy.

Peptides as Therapeutic Agents for Inflammatory-Related Diseases

“…These modifications often determine an enhancement of membranes permeability and an increase of stability to proteolysis by endo and exopeptidases. Another approach implies the substitution of natural amino acid residues with unnatural ones and/or with N-methyl-α-amino acid that also increases plasma stability of the lead compound [ 99 ]. Further budding peptide technologies, including multifunctional peptides, cell penetrating peptides, and peptide drug conjugates, will facilitate the applicability of peptides as therapeutics in the treatment of inflammation disorders, and even beyond.…”

Peptide-Based Drugs and Drug Delivery Systems

“…Along the same lines, new insight into the most recent advances in chemical modifications of amino acid sequences, linkers and chelators to produce optimal moieties for diagnosis and therapy of human neoplastic diseases was provided by the valuable review of Tornesello et al [ 26 ]. Many synthetic peptides developed for diagnosis and therapy of human cancers based on their ability to target specific receptors overexpressed on cancer cell surface or to penetrate the cell membrane are reviewed.…”

From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery

“…Bombesin is a peptide composed of 14 amino acids (EQRLGNQWAVGHLM-NH 2 ), isolated from the poisonous skin of the frog Bombina bombina, that shows high affinity for gastrin-releasing peptide-receptors (Tornesello et al, 2017;Utkin, 2017). Overexpression of members of this receptor family has been documented in several human neoplasms, such as prostate cancer, breast cancer, and small cell lung cancer.…”

“…It is an imaging agent for positron emission tomography/magnetic resonance imaging and attaches to tumor cells with specific receptors on their surfaces (NCT02440308). Different chemical modifications have been introduced in the synthetic bombesin to stabilize its structure, increase the binding affinity and to potentiate its agonist/antagonist properties (Cescato et al, 2008;Tornesello et al, 2017). A large variety of bombesin receptor ligands have been preclinically tested, most of which were bombesin agonists (Baratto et al, 2018).…”