Doctor of Philosophy, University of Akron (2021)
Master of Science, University of Science and Technology Beijing (2017)
Danny Chou, Postdoctoral Faculty Sponsor
Antagonistic Insulin Derivative Suppresses Insulin-Induced Hypoglycemia.
Journal of medicinal chemistry
Insulin derivatives provide new functions that are distinctive from native insulin. We investigated insulin modifications on the C-terminal A chain with insulin receptor (IR) peptide binders and presented a full and potent IR antagonist. We prepared insulin precursors featuring a sortase A (SrtA) recognition sequence, LPETGG, at the C-terminal A chain and used a SrtA-mediated ligation method to synthesize insulin derivatives. The insulin precursor exhibits full IR agonism potency, similar to native human insulin. We explored derivatives with linear IR binding peptides attached to the insulin C-terminal A chain. One insulin derivative with an IR binder (Ins-AC-S2) can fully antagonize IR activation by insulin, as confirmed by cell-based assays. This IR antagonist suppresses insulin-induced hypoglycemia in a streptozotocin-induced diabetic rat model. This study provides a new direction toward insulin antagonist development.
View details for DOI 10.1021/acs.jmedchem.3c00280
View details for PubMedID 37227951
Fundamentals and exploration of aggregation-induced emission molecules for amyloid protein aggregation
JOURNAL OF MATERIALS CHEMISTRY B
2022; 10 (14): 2280-2295
The past decade has witnessed the growing interest and advances in aggregation-induced emission (AIE) molecules as driven by their unique fluorescence/optical properties in particular sensing applications including biomolecule sensing/detection, environmental/health monitoring, cell imaging/tracking, and disease analysis/diagnosis. In sharp contrast to conventional aggregation-caused quenching (ACQ) fluorophores, AIE molecules possess intrinsic advantages for the study of disease-related protein aggregates, but such studies are still at an infant stage with much less scientific exploration. This outlook mainly aims to provide the first systematic summary of AIE-based molecules for amyloid protein aggregates associated with neurodegenerative diseases. Despite a limited number of studies on AIE-amyloid systems, we will survey recent and important developments of AIE molecules for different amyloid protein aggregates of Aβ (associated with Alzheimer's disease), insulin (associated with type 2 diabetes), (α-syn, associated with Parkinson's disease), and HEWL (associated with familial lysozyme systemic amyloidosis) with a particular focus on the working principle and structural design of four types of AIE-based molecules. Finally, we will provide our views on current challenges and future directions in this emerging area. Our goal is to inspire more researchers and investment in this emerging but less explored subject, so as to advance our fundamental understanding and practical design/usages of AIE molecules for disease-related protein aggregates.
View details for DOI 10.1039/d1tb01942b
View details for Web of Science ID 000713405600001
View details for PubMedID 34724699
Antimicrobial alpha-defensins as multi-target inhibitors against amyloid formation and microbial infection
2021; 12 (26): 9124-9139
Amyloid aggregation and microbial infection are considered as pathological risk factors for developing amyloid diseases, including Alzheimer's disease (AD), type II diabetes (T2D), Parkinson's disease (PD), and medullary thyroid carcinoma (MTC). Due to the multifactorial nature of amyloid diseases, single-target drugs and treatments have mostly failed to inhibit amyloid aggregation and microbial infection simultaneously, thus leading to marginal benefits for amyloid inhibition and medical treatments. Herein, we proposed and demonstrated a new "anti-amyloid and antimicrobial hypothesis" to discover two host-defense antimicrobial peptides of α-defensins containing β-rich structures (human neutrophil peptide of HNP-1 and rabbit neutrophil peptide of NP-3A), which have demonstrated multi-target, sequence-independent functions to (i) prevent the aggregation and misfolding of different amyloid proteins of amyloid-β (Aβ, associated with AD), human islet amyloid polypeptide (hIAPP, associated with T2D), and human calcitonin (hCT, associated with MTC) at sub-stoichiometric concentrations, (ii) reduce amyloid-induced cell toxicity, and (iii) retain their original antimicrobial activity upon the formation of complexes with amyloid peptides. Further structural analysis showed that the sequence-independent amyloid inhibition function of α-defensins mainly stems from their cross-interactions with amyloid proteins via β-structure interactions. The discovery of antimicrobial peptides containing β-structures to inhibit both microbial infection and amyloid aggregation greatly expands the new therapeutic potential of antimicrobial peptides as multi-target amyloid inhibitors for better understanding pathological causes and treatments of amyloid diseases.
View details for DOI 10.1039/d1sc01133b
View details for Web of Science ID 000659476200001
View details for PubMedID 34276942
View details for PubMedCentralID PMC8261786
Design and Engineering of Amyloid Aggregation-Prone Fragments and Their Antimicrobial Conjugates with Multi-Target Functionality
ADVANCED FUNCTIONAL MATERIALS
2021; 31 (32)
View details for DOI 10.1002/adfm.202102978
View details for Web of Science ID 000649968900001
Dual amyloid cross-seeding reveals steric zipper-facilitated fibrillization and pathological links between protein misfolding diseases
JOURNAL OF MATERIALS CHEMISTRY B
2021; 9 (15): 3300-3316
Amyloid cross-seeding, as a result of direct interaction and co-aggregation between different disease-causative peptides, is considered as a main mechanism for the spread of the overlapping pathology across different cells and tissues between different protein-misfolding diseases (PMDs). Despite the biomedical significance of amyloid cross-seeding in amyloidogenesis, it remains a great challenge to discover amyloid cross-seeding systems and reveal their cross-seeding structures and mechanisms. Herein, we are the first to report that GNNQQNY - a short fragment from yeast prion protein Sup35 - can cross-seed with both amyloid-β (Aβ, associated with Alzheimer's disease) and human islet amyloid polypeptide (hIAPP, associated with type II diabetes) to form β-structure-rich assemblies and to accelerate amyloid fibrillization. Dry, steric β-zippers, formed by the two β-sheets of different amyloid peptides, provide generally interactive and structural motifs to facilitate amyloid cross-seeding. The presence of different steric β-zippers in a variety of GNNQQNY-Aβ and GNNQQNY-hIAPP assemblies also explains amyloid polymorphism. In addition, alteration of steric zipper formation by single-point mutations of GNNQQNY and interactions of GNNQQNY with different Aβ and hIAPP seeds leads to different amyloid cross-seeding efficiencies, further confirming the existence of cross-seeding barriers. This work offers a better structural-based understanding of amyloid cross-seeding mechanisms linked to different PMDs.
View details for DOI 10.1039/d0tb02958k
View details for Web of Science ID 000641964200013
View details for PubMedID 33651875
Design principles and fundamental understanding of biosensors for amyloid-beta detection
JOURNAL OF MATERIALS CHEMISTRY B
2020; 8 (29): 6179-6196
Alzheimer's disease (AD), as an age-related, progressive neurodegenerative disease, poses substantial challenges and burdens on public health and disease research. While significant research, investment, and progress have been made for the better understanding of pathological mechanisms and risk factors of AD, all clinical trials for AD treatment and diagnostics have failed so far. Since early and accurate diagnostics of AD is key to AD prevention and treatment, the development of probes for AD-related biomarkers is highly important but challenging for AD diagnosis. In this review, emerging evidence highlights the importance of the Aβ cascade hypothesis and indicates a significant role of Aβ and its aggregates as biomarkers in the pathogenesis of AD; we present an up-to-date summary on Aβ-based biosensor systems. Four typical biosensor systems for Aβ detection and representative examples from each type of biosensor are carefully selected and discussed in terms of their sensing strategies, materials, and mechanisms. Finally, we address the remaining challenges and opportunities for the development of future sensing platforms for Aβ detection and Aβ-based diagnostics of AD.
View details for DOI 10.1039/d0tb00344a
View details for Web of Science ID 000553658200010
View details for PubMedID 32355946