Releasable Conjugation of Polymers to Proteins

Abstract

Many synthetic strategies are available for preparing well-defined conjugates of peptides/proteins and polymers. Most reports on this topic involve coupling methoxy poly(ethylene glycol) to therapeutic proteins, a process referred to as PEGylation, to increase their circulation lifetime and reduce their immunogenicity. Unfortunately, the major dissuading dogma of PEGylation is that, in many cases, polymer modification leads to significant (or total) loss of activity/function. One approach that is gaining momentum to address this challenge is to release the native protein from the polymer with time in the body (releasable PEGylation). This contribution will present the state-of-the-art of this rapidly evolving field, with emphasis on the chemistry behind the release of the peptide/protein and the means for altering the rate of release in biological fluids. Linkers discussed include those based on the following: substituted maleic anhydride and succinates, disulfides, 1,6-benzyl-elimination, host-guest interactions, bicin, β-elimination, biodegradable polymers, E1cb elimination, β-alanine, photoimmolation, coordination chemistry, zymogen activation, proteolysis, and thioesters.

Organic Arsenicals As Efficient and Highly Specific Linkers for Protein/Peptide–Polymer Conjugation

“…63 Following reduction to As(III), the affinity of the soft metalloid center for dithiols was exemplified by rapid chelation to ethanedithiol to form the cyclic dithiaarsane, which was also prepared in a one-pot process (Scheme 1). 64 For thermodynamic reasons, the dithiaarsanes were not considered for conjugation with attention focused on the arsenous acid (As(III)) functionality.…”

Boronic Acid for the Traceless Delivery of Proteins into Cells

“…1 Extensive efforts have led to the development of effective delivery systems that invoke cell-penetrating peptides, 2–5 antibodies, 6 ligands for natural receptors, 7 dendrimers, 8 functionalized polymers, 9,10 liposomes, 11 or nanoparticles. 12,13 Extant strategies can, however, lead to adducts that are inapplicable in vivo , unstable in a physiological context, recalcitrant to biodegradation, or immunogenic.…”

“…19 The ensuing formation of transient boronate esters with the glycocalyx enhances cellular delivery. To date, this approach has relied on the irreversible modification of the target protein, which can compromise activity 20,19,10,21 or lead to immunogenicity. 22,23 An ideal delivery system based on boronic acids (or any moiety) is “traceless” in its delivery of cargo.…”

Disulfide Conjugation Chemistry: A Mixed Blessing for Therapeutic Drug delivery?

“…Despite providing stealth, prolonging circulation life times and reducing immunogenicity of these therapeutics, clinical limitations of PEG conjugation (PEGylation) include its nondegradability. Additionally, maintaining biological activity after conjugation remains a challenge particularly when conjugating polymers to peptides, proteins with macromolecular substrates or proteins that bind substrates requiring a large proportion of its solvent-exposed surface [3,4]. Similarly, permanent polymer conjugation to small molecule inhibitors often results in reduced potencies [5].…”