Feature Collection in Peptide Therapeutics: Current Applications and Future Directions

Peptide-based medicines have been an important segment of the pharmaceutical market for a few decades, with applications in the treatment of a large number of diseases. Several have become “blockbusters”, such as the Sanofi Lantus^TM recombinant insulin for the treatment of diabetes. More recently, Eli Lilly and Novo Nordisk GLP-1 (glucagon-like peptide-1) receptor agonists, initially developed for type-2 diabetes, have been approved to treat obesity for patients at risk of cardiovascular diseases with a large commercial success.

The still-increasing interest in peptide-based medicines has been driven by their highly specific action and their capacity to reach targets that are difficult or impossible to tackle with conventional low-molecular-weight drugs. However, the short metabolic stability of natural peptides, their poor oral bioavailability, their low membrane permeability, and their synthesis cost proved to be limitations for many clinical applications. Nevertheless, more than 100 peptides have been approved by regulatory agencies, and many undergo clinical development.

The present “Feature Collection in Peptide Therapeutics” aims to focus on selected peptide classes and on several strategies to improve their therapeutic efficacy since the field is by far too large to be covered comprehensively. First, we will restrict peptides to less than fifty amino acids, thus excluding therapeutic proteins and antibodies despite their numerous and important clinical applications. As pointed out above, peptides offer unique possibilities to modulate targets considered undruggable by low-molecular-weight drugs.

Large-scale screenings with cell biology-based technologies or computational strategies have led to the unraveling of protein interactomes. Most biological processes are now considered to be regulated by complex protein–protein interactions (PPIs). An estimated number of 600,000 PPIs in humans has been proposed. Most PPIs are considered undruggable since interfaces between proteins generally involve large surfaces (at variance with receptor–ligand interactions) often formed between discontinuous sets of amino acids, thus lacking well-defined binding sites for low molecular mass drugs. While still in its infancy, the field provides many potential targets for peptide drug design and development.

The weaknesses of peptide-based drugs mentioned above will hopefully benefit from progress in medicinal chemistry and SAR (structure–activity relationship) studies. Amino acid modifications, incorporation of unnatural amino acids, cyclizations, conjugation with various chemical entities, or encapsulation in non-viral delivery vectors represent interesting strategies to improve pharmacological properties, reduce degradation by proteases, or increase membrane permeability. Cyclosporin A is a typical example of the potential of modified cyclic peptides as drugs.

Antimicrobial peptides (AMPs) constitute another class of drugs with potentially important developments in view of the great threat represented by microbial infections, for which drugs are not available or are no longer efficient with the increasing number of antibiotic multi-resistant strains. Interestingly, AMPs are produced by nearly all living species as a first line of defense against pathogens, with gramicidin as an example of clinical application. Delineating more accurately their mode of action (and in particular their interactions with the membranes of pathogens), increasing their production and potential, decreasing their side effects, and enlarging their spectrum of action will lead to interesting developments and hopefully bring an increasing number of AMPs to clinics.

Most weaknesses of peptide-based strategies might potentially be addressed through association or encapsulation with delivery vectors. Naturally occurring or synthetic cell-penetrating peptides (CPPs) have received considerable attention in the last decades in view of their capacity to deliver a macromolecular payload (peptides or nucleic acids) across biological membranes, whether chemically conjugated or associated non-covalently. Direct translocation and endocytosis through non-receptor dependent mechanisms have both been proposed. A better understanding will hopefully allow improvements, such as, for instance, the endosomal release of the transported drugs. The lack of cell specificity for naturally occurring CPPs is another limitation. Interesting developments include CPP modifications leading to the delivery of their payloads in a specific environment, for instance, through tumor cell-associated enzymes. Other strategies have involved the selection of cell-specific CPPs from peptide phage display libraries.

Contributions with reviews or original articles documenting the strategies briefly outlined above are welcomed. This list is, however, not restrictive, and innovative alternative proposals will be examined by the editors.

Dr. Bernard Lebleu
Guest Editor

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• peptide-based drugs
• protein–protein interactions
• antimicrobial peptides
• cell-penetrating peptides
• peptide delivery
• cell-targeting peptides