Non-Covalent Albumin Ligands in FDA-Approved Therapeutic Peptides and Proteins

Abstract

An increasing number of drugs that consist of a therapeutic peptide or protein linked to an albumin-binding structure are being approved. In this perspective, the pharmacokinetic data of currently marketed drugs of this type will be presented. Acylation with fatty acids or fatty α,ω-dicarboxylic acids has been used successfully to prepare long-acting analogs of insulin, GLP-1, and other peptides but not of larger proteins. With a tetrazole-sulfonylamide fatty acid bioisostere, it has now been possible to prepare a long-acting analog of human growth hormone (191 amino acids), which is suitable for once-weekly administration.

Discovery of Novel PTP1B Inhibitors with Once-Weekly Therapeutic Potential for Type 2 Diabetes: Design, Synthesis, and In Vitro and In Vivo Investigations of BimBH3 Peptide Analogues

“…Our previous work also indicated that the modification of the N-terminal of the 12-mer BimBH3 peptide and the attached groups played a key role in the PTP1B inhibitory activity. We aim to generate BimBH3 peptide analogues with improved stability and efficacy suitable for long-acting s.c. administration without compromising the potency and design analogues 1 – 35 (Table ) via N-terminal lipidation/acylation with alkyl carboxylic and fatty acids/diacids (Figure ), attempting to improve their stability toward enzymatic degradation and long-acting profile in vivo . The analogues were synthesized by Fmoc-based solid-phase peptide synthesis (SPPS) on 2-Cl-CTC resin and cleaved from resin thereafter, obtaining the desired peptides.…”

“…Moreover, the phosphorylated Bad-BH3 domain and/or hydrocarbon-stapled Bad-BH3 mimetics originally designed as Bcl-2/Bcl-xL inhibitors for cancer-killing were found to exhibit therapeutic potency in diabetes through targeting glucokinase, restoring glucose-driven mitochondrial respiration and correcting the insulin secretory, − whereas the therapeutic potential of biologically active peptides is usually constrained by several limitations such as low oral bioavailability, poor pharmacokinetics behavior, and low plasma stability. Among the numerous strategies adopted to improve the pharmacological profiles of peptides, lipidation strategy has proven to be robust and effective in improving the therapeutic potential of peptide therapeutics. − As mentioned above, the GLP-1 RAs lliraglutide, semaglutide, and the dual GIP/GLP-1 receptor agonist tirzepatide were successful examples of lipidated peptide therapeutics, which increased investments in the field and expanded the market of peptide-based therapeutics. ,− Generally speaking, the lipidation of peptides can dramatically enhance their receptor selectivity, enzymatic stability, and bioavailability. The lapidated peptides that have been successfully marketed usually showed more resistance to enzymatic degradation and were linked to an albumin ligand to prolong their duration of action.…”

Developing a Hetero-Trinuclear Erbium(III)–Copper(II) Complex Based on Apoferritin: Targeted Photoacoustic Imaging and Multimodality Therapy of Tumor

“…Previous studies showed that metal complexes could induce autophagy of cancer cells. , Therefore, we examined the level of autophagy induced by ErCu 2 and ErCu 2 @AFt NPs using green fluorescent protein (GFP)-fused LC3 (a specific label for autophagosome formation). As indicated in Figure A, the generation of GFP-LC3-labeled vacuoles in the MDA-MB-231 cell line was enhanced after incubation with ErCu 2 compared with control and AFt NPs + NIR groups.…”

“…At the same time, we should overcome the shortcomings of metal complexes, such as lack of targeting ability and significant off-target toxicity, which brought out serious systemic toxicity in vivo . At present, protein-based drug delivery systems have been one of the most promising strategies to overcome these shortcomings. − Indeed, apoferritin (AFt) is an ideal candidate due to its nanoscale structure, biocompatibility, biodegradability, and nontoxicity. − …”

Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin–Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment

“…There are two main challenges to this approach: (1) how to solve the codelivery problems of the Cu compound and IND in vivo and (2) how to improve the targeting ability of the Cu compound and IND and decrease their side effects in vivo . Since human serum albumin (HSA) is the most abundant endogenous protein in blood, HSA has become one of the most promising carriers to meet the above-mentioned challenges. − In addition, because HSA has several binding sites that can bind different types of compounds, ,,, we can construct an innovative HSA–drug complex delivery system based on the properties of HSA. ,,− …”