Yanxian Zhang

All Publications

• From Natural Insulin to Designed Analogs: A Chemical Biology Exploration. Chembiochem : a European journal of chemical biology Zhang, Y., Hung-Chieh Chou, D. 2023: e202300470

  Abstract

  Since its discovery in 1921, insulin has been at the forefront of scientific breakthroughs. From its amino acid sequencing to the revelation of its three-dimensional structure, the progress in insulin research has spurred significant therapeutic breakthroughs. In recent years, protein engineering has introduced innovative chemical and enzymatic methods for insulin modification, fostering the development of therapeutics with tailored pharmacological profiles. Alongside these advances, the quest for self-regulated, glucose-responsive insulin remains a holy grail in the field. In this article, we highlight the pivotal role of chemical biology in driving these innovations and discuss how it continues to shape the future trajectory of insulin research.

  View details for DOI 10.1002/cbic.202300470

  View details for PubMedID 37800626

• Antagonistic Insulin Derivative Suppresses Insulin-Induced Hypoglycemia. Journal of medicinal chemistry Park, C., Zhang, Y., Jung, J. U., Buron, L. D., Lin, N. P., Hoeg-Jensen, T., Chou, D. H. 2023

  Abstract

  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

• Supramolecular approaches for insulin stabilization without prolonged duration of action. Acta pharmaceutica Sinica. B Meudom, R., Zhang, Y., VandenBerg, M. A., Zou, L., Zhang, Y. W., Webber, M. J., Chou, D. H. 2023; 13 (5): 2281-2290

  Abstract

  Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics. The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol (CB[7]‒PEG) has been shown to stabilize insulin formulations by reducing aggregation propensity. Yet prolonged invivo duration of action, arising from sustained complex formation in the subcutaneous depot, limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal. Supramolecular affinity of CB[7] in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach. Accordingly, here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7] interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation. These insulin analogs show weak to no interaction with CB[7]‒PEG at physiological pH but demonstrate high formulation stability at reduced pH. Accordingly, N-terminal modified analogs have invitro and invivo bioactivity comparable to native insulin. Furthermore, in a rat model of diabetes, the acid-modified insulin formulated with CB[7]‒PEG offers a reduced duration of action compared to native insulin formulated with CB[7]‒PEG. This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging invivo duration of action.

  View details for DOI 10.1016/j.apsb.2023.01.007

  View details for PubMedID 37250160

• Fundamentals and exploration of aggregation-induced emission molecules for amyloid protein aggregation JOURNAL OF MATERIALS CHEMISTRY B Tang, Y., Zhang, D., Zhang, Y., Liu, Y., Cai, L., Plaster, E., Zheng, J. 2022; 10 (14): 2280-2295

  Abstract

  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 CHEMICAL SCIENCE Zhang, Y., Liu, Y., Tang, Y., Zhang, D., He, H., Wu, J., Zheng, J. 2021; 12 (26): 9124-9139

  Abstract

  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 Zhang, Y., Tang, Y., Liu, Y., Zhang, D., Zheng, J. 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 Zhang, Y., Zhang, M., Liu, Y., Zhang, D., Tang, Y., Ren, B., Zheng, J. 2021; 9 (15): 3300-3316

  Abstract

  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 Zhang, Y., Ren, B., Zhang, D., Liu, Y., Zhang, M., Zhao, C., Zheng, J. 2020; 8 (29): 6179-6196

  Abstract

  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