Peptidomimetic-based antibody surrogate for HER2

Abstract

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on γ -AApeptides to target HER2 extracellular domain (ECD). To achieve this, we synthesized a one-bead-two-compound (OBTC) library containing 320,000 cyclic γ -AApeptides, from which we identified a γ -AApeptide, M-3-6, that tightly binds to HER2 selectively. Subsequently, we designed an antibody-like dimer of M-3-6, named M-3-6-D, which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies. Intriguingly, M-3-6-D was completely resistant toward enzymatic degradation. In addition, it could effectively inhibit the phosphorylation of HER2, as well as the downstream signaling pathways of AKT and ERK. Furthermore, M-3-6-D also efficiently inhibited cell proliferation in vitro , and suppressed tumor growth in SKBR3 xenograft model in vivo , implying its therapeutic potential for the treatment of cancers. Its small molecular weight, antibody-like property, resistance to proteolysis, may enable it a new generation of artificial antibody surrogate. Furthermore, our strategy of artificial antibody surrogate based on dimers of cyclic γ -AApeptides could be applied to a myriad of disease-related receptor targets in future.

A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein

“…Meanwhile, Cai’s group previously established several cyclic γ-AApeptide-based OBTC combinatorial libraries in which the cyclic γ-AApeptides possess high proteolytic enzyme stability and potent biological activity 26 – 30 . For example, several cyclic γ-AApeptides were identified to target EphA2, EGFR, and HER2 with excellent binding affinity and specificity 27 , 30 , 31 . Therefore, it is feasible to identify some γ-AApeptide-based pan-CoV fusion inhibitors with oral bioavailability.…”

“…Cai’s group has established several cyclic γ-AApeptide-based one-bead-two-compound (OBTC) combinatorial libraries in which the cyclic γ-AApeptides possess high proteolytic enzyme stability and good oral availability 26 – 30 . Through screening these OBTC libraries, several important hits, such as cyclic γ-AApeptides targeting EphA2, EGFR and HER2 were identified 27 , 30 , 31 , suggesting that these libraries can be used for identification of γ-AApeptide-based pan-CoV fusion inhibitors with oral bioavailability.…”

Application of the Nicoya OpenSPR to Studies of Biomolecular Binding: A Review of the Literature from 2016 to 2022

“…There are a wide variety of reasons investigators use SPR, and some of the most common applications are assessing the binding of a potential therapeutic to its target [ 33 , 37 , 44 , 53 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 65 , 66 , 67 , 80 , 84 , 169 , 176 , 179 , 181 , 207 ] or to measure the affinity of a potential inhibitor [ 23 , 25 , 46 , 86 , 89 , 98 , 105 , 114 , 115 , 123 , 133 , 143 , 148 , 158 , 159 , 171 , 182 , 186 , 187 , 204 ]. The proposed therapeutics were sometimes novel compounds, such as the tasine derivate compounds synthesized by Yang and coworkers to suppress HeLa cells [ 33 ] or the bioactive iridium metal-complex developed by Ji et al to eliminate excess reactive oxygen species (ROS) induced by spinal cord injuries (SCI) [ 179 ].…”

α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo

“…These features have enabled γ -AApeptides to exert biological potential in chemical biology and biomedical sciences 36 . For instance, their functional diversity and modular synthesis have led to the creation of γ -AApeptides based combinatorial libraries that facilitated identification of drug candidates and molecular probes 39 , 40 , 41 , 42 , 43 , 44 , whereas the robust folding conformation of sulfono- γ -AApeptides empower them ideal foldamer candidates for the recognition of proteins and modulation of protein‒protein interactions (PPIs) 16 , 37 , 45 , 46 , 47 , 48 . Indeed, we have previously designed GLP-1 mimetics based on homogeneous sulfono- γ -AApeptides ( Fig.…”