Lipidization as a tool toward peptide therapeutics

Abstract

Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.

Keywords:

• Peptide therapeutics
• structure modification
• lipidization
• therapeutic lipopeptides

Authors’ contributions

A.M. was involved in the conception and drafting of the manuscript including figures, D.S. participated in drafting the manuscript, he made final revisions and approval of the manuscript version submitted, J.K. revised the manuscript, and L.M. revised the manuscript. All authors agree to be accountable for all aspects of the work.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by the Czech Science Foundation, projects 21-03691S, 22-11155S, and by the Czech Academy of Sciences, projects RVO: 61388963 and RVO: 67985823.