Abstract
Simple SummaryPeptide drugs that can specifically target undesirable protein–protein interactions that lead to oncogenic developments have emerged as the next era of future medicine for cancers. To combat GBM tumor progression, our study offers an alternative therapeutic strategy via targeting the protein–protein interaction between MSI1 and AGO2 with synthetic peptides identified from the C-terminus of MSI1 in peptide arrays. Our present data revealed for the first time that peptidic disruption to the MSI1/AGO2 complex known for promoting cancer stemness and progression could lead to encouraging therapeutic efficacy at both in vitro and in vivo levels. The significantly suppressed tumor growth and prolonged survival rates in PDX tumor models by decoy peptides evidently provided a new rationale for stratifying patients with MSI1/AGO2-targeted therapeutics.Peptide drugs that target protein–protein interactions have attracted mounting research efforts towards clinical developments over the past decades. Increasing reports have indicated that expression of Musashi 1 (MSI1) is tightly correlated to high grade of cancers as well as enrichment of cancer stem cells. Treatment failure in malignant tumors glioblastoma multiform (GBM) had also been correlated to CSC-regulating properties of MSI1. It is thus imperative to develop new therapeutics that could effectively improve current regimens used in clinics. MSI1 and AGO2 are two emerging oncogenic molecules that both contribute to GBM tumorigenesis through mRNA regulation of targets involved in apoptosis and cell cycle. In this study, we designed peptide arrays covering the C-terminus of MSI1 and identified two peptides (Pep#11 and Pep#26) that could specifically interfere with the binding with AGO2. Our Biacore analyses ascertained binding between the identified peptides and AGO2. Recombinant reporter system Gaussian luciferase and fluorescent bioconjugate techniques were employed to determine biological functions and pharmacokinetic characteristics of these two peptides. Our data suggested that Pep#11 and Pep#26 could function as decoy peptides by mimicking the interaction function of MSI1 with its binding partner AGO2 in vitro and in vivo. Further experiments using GMB animal models corroborated the ability of Pep#11 and Pep#26 in disrupting MSI1/AGO2 interaction and consequently anti-tumorigenicity and prolonged survival rates. These striking therapeutic efficacies orchestrated by the synthetic peptides were attributed to the decoy function to C-terminal MSI1, especially in malignant brain tumors and glioblastoma.
Highlights
Protein-targeting drugs including various monoclonal antibodies have been proven therapeutically effective in clinics and accumulating evidence suggests targeting protein–protein interactions that lead to oncogenic developments may be the era of future medicine for cancers [1,2]
Musashi 1 (MSI1) has emerged as an oncogenic protein that functions as a stem cell determinant to promote cancer cell survival, tumor progression, and its expression is closely correlated to drug resistance and cancer relapse in patients [33,34]
We designed peptide arrays in an attempt to discover whether any motifs within the MSI1 C-terminus could act as decoy peptides that are critical for protein–protein interaction with AGO2 (Figure 2A)
Summary
Protein-targeting drugs including various monoclonal antibodies have been proven therapeutically effective in clinics and accumulating evidence suggests targeting protein–protein interactions that lead to oncogenic developments may be the era of future medicine for cancers [1,2]. Similar molecular dynamics strategies had been applied and led to the discovery of Herstatin, a peptide composed of partial HER2 ectodomain that functioned to auto-inhibit HER2-mediated signaling [8] Another series of peptides designed by molecular dynamics modeling that targets HER2 was shown to be at submicro molarities of dissociation constant (KD ) that served as a specific probe by molecular imaging for HER2-positive tumors [9]. To date, such strategies of identifying crucial motifs to disrupt homo- or hetero-dimerization of EGFRs are increasingly proven to be of great potential for clinical use
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