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

Abstract

Poor medication adherence in patients with type 2 diabetes mellitus has become one of the main causes of suboptimal glycemic control. Once-weekly drugs can markedly improve the convenience, adherence, and quality of life of T2DM patients; thus, they are clinically needed and preferred. PTP1B plays a negative role in both insulin and leptin signaling pathways, which makes it an important target for diabetes. Herein, we design and synthesize 35 analogues of core BimBH3 peptide via lipidation/acylation strategy based on our previous work and evaluate their PTP1B inhibitory activity, obtaining the primary structure–activity relationship. Five compounds with good PPT1B inhibitory activity, target selectivity, and significantly improved stability were selected for molecular docking study and searching candidate molecules with long-acting antidiabetic potential. The in vivo anti-T2DM evaluation validated the once-weekly therapeutic potential of analogues 19, 26, 27, 31, and 33, which were comparable with semaglutide and therefore presented as promising drug candidates.

Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity

“…The peptide analogues were synthesized using the Fmocbased solid-phase peptide synthesis (SPPS) strategy on 2-Cl-CTC resin as described previously. 54,70 The crude analogues were purified by semipreparative high-performance liquid chromatography (HPLC) using C 18 columns, and the purified analogues were determined by electrospray ionization-mass Target Inhibitory Activity and SAR. The in vitro enzyme-based inhibitory activity against human recombinant PTP1B and TC-PTP of the BimBH3 analogues was evaluated using the procedure as described previously.…”

“…The crystal structure of PTP1B (PDB ID: 5K9V) and TC-PTP (PDB ID: 7UAD) was obtained from the protein data bank, and the docking method and procedure were conducted as previously described. 54 The docking of BimBH3 analogue-PTP1B complexes was performed with the MOE function at standard settings (T = 300 K, pH 7.0). The molecular docking results are shown in Figure 2.…”

“…35 In our previous work, a class of novel PTP1B inhibitors derived from the core BimBH3 peptide via Nterminal derivatization with fatty acids and their once-weekly therapeutic potential for T2DM were reported. 54 The peptides and/or proteins modified with fatty acids have now been successfully applied to engineer plenty of long-acting biopharmaceuticals, 55 such as the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, 56 once-weekly GIP/ GLP-1 dual agonist tirzepatide, 57 and once-weekly insulin analogue icodec. 58 Reports from the International Diabetes Federation (IDF) Diabetes Atlas 10th edition indicate that diabetes mellitus has escalated into one of the most pressing global health crises, 59 and by 2050, more than 1.31 billion people are predicted to have diabetes according to the global burden of disease study 2021.…”

“…68 Our recently reported PTP1B inhibitors derived from the BimBH3 peptide (Figure 1a) with long-acting antidiabetic potency have been proven to be a new class of potent once-weekly antidiabetic drugs, and these compounds seem to be more attractive and advantageous because of their shorter sequence and direct N-terminal fatty acid lipidation, resulting in markedly lower production costs compared with that of semaglutide and tirzepatide. 54 However, the structure−activity relationship (SAR) study of BimBH3 peptide analogues is insufficient because the role of each amino acid in the 12-mer peptide is still not fully understood. In addition, the 12-mer BimBH3 peptide is theoretically susceptible to dipeptidyl peptidase-IV (DPP-IV) degradation due to the second position in the N terminus of Ala, just similar to native GLP-1, liraglutide, and semaglutide.…”

Influence of Fatty Acid Modification on the Anticancer Activity of the Antimicrobial Peptide Figainin 1

“…For example, antimicrobial peptides can inhibit tumor cell proliferation by inducing apoptosis. , Unfortunately, the instability of this peptide leads to it having poor pharmacokinetic properties . Various design strategies have been developed to improve the stability of antimicrobial peptides, such as modification with unnatural amino acids, lipidation, cyclization, peptidomimetics, and nanotechnology. − Lipidation generally refers to the attachment of fatty acids to the N-terminal or Lys residues of antimicrobial peptides . Lipidation can increase the stability of antimicrobial peptides by blocking the region vulnerable to proteases or forming a supramolecular structure, further prolonging the effective time of the antimicrobial peptide drug. , Lipidation is a useful modification to tune the proteolytic stability and antibacterial activity of antimicrobial peptides.…”