Conjugates for use in peptide therapeutics: A systematic review and meta-analysis

Abstract

While peptides can be excellent therapeutics for several conditions, their limited in vivo half-lives have been a major bottleneck in the development of therapeutic peptides. Conjugating the peptide to an inert chemical moiety is a strategy that has repeatedly proven to be successful in extending the half-life of some therapeutics. This systematic review and meta-analysis was conducted to examine the available literature and assess it in an unbiased manner to determine which conjugates, both biological and synthetic, provide the greatest increase in therapeutic peptide half-life. Systematic searches run on PubMed, Scopus and SciFinder databases resulted in 845 studies pertaining to the topic, 16 of these were included in this review after assessment against pre-specified inclusion criteria registered on PROSPERO (#CRD42020222579). The most common reasons for exclusion were non-IV administration and large peptide size. Of the 16 studies that were included, a diverse suite of conjugates that increased half-life from 0.1 h to 33.57 h was identified. Amongst these peptides, the largest increase in half-life was seen when conjugated with glycosaminoglycans. A meta-analysis of studies that contained fatty acid conjugates indicated that acylation contributed to a statistically significant extension of half-life. Additionally, another meta-analysis followed by a sensitivity analysis suggested that conjugation with specifically engineered recombinant peptides might contribute to a more efficient extension of peptide half-life as compared to PEGylation. Moreover, we confirmed that while polyethylene glycol is a good synthetic conjugate, its chain length likely has an impact on its effectiveness in extending half-life. Furthermore, we found that most animal studies do not include as much detail when reporting findings as compared to human studies. Inclusion of additional experimental detail on aspects such as independent assessment and randomization may be an easily accomplished strategy to drive more conjugated peptides towards clinical studies.

A Brief Guide to Preparing a Peptide–Drug Conjugate

“…[1,2] Recently, peptide-drug conjugates (PDCs) have emerged as interesting tools for cancer-targeted therapy and some representatives of this class are already in clinical trials. [3,4] In particular, two PDCs are currently on the market: melfuflen for the treatment of multiple myeloma and lutathera for the therapy of gastroenteropancreatic neuroendocrine tumours.…”

“…Targeted therapy represents an emerging paradigm for the current biomedical research, as selective and precise delivery of drugs to diseased tissues can be a good strategy to improve the therapeutic efficiency of the drug/probe, to overcome drug resistance, to reduce the off‐target effects and to early detect several diseased states [1,2] . Recently, peptide–drug conjugates (PDCs) have emerged as interesting tools for cancer‐targeted therapy and some representatives of this class are already in clinical trials [3,4] . In particular, two PDCs are currently on the market: melfuflen for the treatment of multiple myeloma and lutathera for the therapy of gastroenteropancreatic neuroendocrine tumours.…”

Development of New Leishmanicidal Compounds via Bioconjugation of Antimicrobial Peptides and Antileishmanial Guanidines

“…Numerous studies have demonstrated the effectiveness of this strategy in developing antimicrobial, anticancer, antifungal, 15−17 and antileishmanial 18,19 compounds. Peptide conjugation is a comprehensive strategy employed to enhance the selectivity and potency of peptides, 20 thereby bolstering the benefits of peptide-based pharmacology with medicinal chemistry. 21 The conjugates utilized in peptide therapeutics may comprise poly(ethylene glycol), ferrocene, lipids, or other molecular types.…”

“…Peptide conjugation is a comprehensive strategy employed to enhance the selectivity and potency of peptides, thereby bolstering the benefits of peptide-based pharmacology with medicinal chemistry . The conjugates utilized in peptide therapeutics may comprise poly­(ethylene glycol), ferrocene, lipids, or other molecular types.…”

Liposomal Entrapment or Chemical Modification of Relaxin2 for Prolongation of Its Stability and Biological Activity

“…Conjugating the peptide to an inert chemical moiety is one of the strategies repeatedly proven to be successful in extending the half-life of various peptide therapeutics [ 9 ]. More specifically, a meta-analysis of studies that involved fatty acid conjugates of peptides indicated that acylation contributed to a statistically significant extension of the half-life of the peptides [ 12 ]. The replacement of disulfide bonds with non-reducible elements has been demonstrated to be effective and to eliminate the relaxin-specific deleterious effect of serum reductases.…”