Bio


Wilford Zhiyu Wang is a Postdoctoral Scholar in the Department of Neurosurgery, School of Medicine. He received his Ph.D. degree from University of Toronto in 2021 and joined Stanford in 2022. His research focuses on the drug discovery for the proteopathy and immunopathy of Alzheimer's disease. As a novel approach, his study intends to ameliorate disease progression through the immune system using small molecules. He identified one novel anti-inflammatory compound that enhances autophagy through mTOR and promotes ER-turnover through TEX264 during Alzheimer-associated neuroinflammation.
He has strong interest in Alzheimer-related research, including toxic protein misfolding and neuroinflammation. He is currently working on the assay developments for hit identification, target engagement, and mechanism-of-action (MOA) study, aiming to identify a drug candidate for neurological disorders.

Honors & Awards


  • COVID-19 student engagement award, University of Toronto (June-2020)
  • Young Investigator Scholarship, Alzheimer's Drug Discovery Foundation (September-2019)
  • Biophysical Chemistry, Molecular Toxicology and Neuroscience Group Poster Award, University of Toronto (June-2019)
  • Ontario Graduate Student Scholarship, Ontario Province of Canada (September-2018)
  • Krembil Research Studentship Award, University Health Network (September-2018)

Professional Education


  • Master of Applied Science(s), University of Ottawa (2015)
  • Doctor of Philosophy, University of Toronto (2021)
  • Doctorate, University of Toronto, Neuroscience and Medicinal Chemistry (2021)

Stanford Advisors


Patents


  • "United StatesFurosemide analogues and compositions and uses thereof for treatment of Alzheimer's Disease"
  • "United StatesFurosemide as a supportive therapy for COVID-19 infection"

Research Interests


  • Brain and Learning Sciences

All Publications


  • Anti-Inflammatory Anthranilate Analogue Enhances Autophagy through mTOR and Promotes ER-Turnover through TEX264 during Alzheimer-Associated Neuroinflammation ACS CHEMICAL NEUROSCIENCE Wang, Z., Huang, J., Yang, S., Weaver, D. F. 2022; 13 (3): 406-422

    Abstract

    Autophagy degrades impaired organelles and toxic proteins to maintain cellular homeostasis. Dysregulated autophagy is a pathogenic participant in Alzheimer's disease (AD) progression. In early-stage AD, autophagy is beneficially initiated by mild endoplasmic reticulum (ER) stress to alleviate cellular damage and inflammation. However, chronic overproduction of toxic Aβ oligomers eventually causes Ca2+ dysregulation in the ER, subsequently elevating ER-stress and impairing autophagy. Our previous work showed that a novel anthranilate analogue (SI-W052) inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 on microglia. To investigate its mechanism of action, herein, we postulate that SI-W052 exhibits anti-inflammatory activity through ER-stress-mediated autophagy. We initially demonstrate that autophagy inhibits inflammation, but it becomes impaired during acute inflammation. SI-W052 significantly induces the conversion ratio of LC3 II/I and inhibits LPS-upregulated p-mTOR, thereby restoring impaired autophagy to modulate inflammation. Our signaling study further indicates that SI-W052 inhibits the upregulation of ER-stress marker genes, including Atf4 and sXbp1/tXbp1, explaining compound activity against IL-6. This evidence encouraged us to evaluate ER-stress-triggered ER-phagy using TEX264. ER-phagy mediates ER-turnover by the degradation of ER fragments to maintain homeostasis. TEX264 is an important ER-phagy receptor involved in ATF4-mediated ER-phagy under ER-stress. In our study, elevated TEX264 degradation is identified during inflammation; SI-W052 enhances TEX264 expression, producing a positive effect in ER-turnover. Our knockdown experiment further verifies the important role of TEX264 in SI-W052 activity against IL-6 and ER-stress. In conclusion, this study demonstrates that an anthranilate analogue is a novel neuroinflammation agent functioning through ER-stress-mediated autophagy and ER-phagy mechanisms.

    View details for DOI 10.1021/acschemneuro.1c00818

    View details for Web of Science ID 000746854500001

    View details for PubMedID 35061945

  • Design, synthesis, and biological evaluation of furosemide analogs as therapeutics for the proteopathy and immunopathy of Alzheimer's disease EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Wang, Z., Wang, Y., Pasangulapati, J., Stover, K. R., Liu, X., Schier, S., Weaver, D. F. 2021; 222: 113565

    Abstract

    β-Amyloid (Aβ) triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer's disease (AD). Monomeric Aβ is derived from amyloid precursor protein, whereupon it aggregates into various assemblies, including oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic/synaptotoxic, but may also induce neuroinflammation through the concomitant activation of microglia. Previously, we have shown that furosemide is a known anthranilate-based drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype. To further explore the pharmacologic effects of furosemide, this study reports a series of furosemide analogs that target both Aβ aggregation and neuroinflammation, thereby addressing the combined proteopathic-immunopathic pathogenesis of AD. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibited Aβ oligomerization; 33 and 34 inhibited Aβ fibrillization. 3g and 34 inhibited the production of TNF-α, IL-6, and nitric oxide, downregulated the expression of COX-2 and iNOS, and promoted microglial phagocytotic activity, suggesting dual activity against Aβ aggregation and neuroinflammation. Our data demonstrate the potential therapeutic utility of the furosemide-like anthranilate platform in the development of drug-like molecules targeting both the proteopathy and immunopathy of AD.

    View details for DOI 10.1016/j.ejmech.2021.113565

    View details for Web of Science ID 000685593800012

    View details for PubMedID 34118718

  • Furosemide as a Probe Molecule for the Treatment of Neuroinflammation in Alzheimer's Disease ACS CHEMICAL NEUROSCIENCE Wang, Z., Vilekar, P., Huang, J., Weaver, D. F. 2020; 11 (24): 4152-4168

    Abstract

    The accumulation and deposition of β-amyloid (Aβ) is one postulated cause of Alzheimer's disease (AD). In addition to its direct toxicity on neurons, Aβ may induce neuroinflammation through the concomitant activation of microglia. Emerging evidence suggests that microglia-mediated neuroinflammation plays an important role in the pathogenesis of AD. As brain macrophages, microglia engulf misfolded-Aβ by phagocytosis. However, the accumulated toxic Aβ may paradoxically "hyper-activate" microglia into a neurotoxic proinflammatory and less phagocytotic phenotype, contributing to neuronal death. This study reports that the known drug furosemide is a potential probe molecule for reducing AD-neuroinflammation. Our data demonstrate that furosemide inhibits the secretion of proinflammatory TNF-α, IL-6, and nitric oxide; downregulates the mRNA level of Cd86 and the protein expression of COX-2, iNOS; promotes phagocytic activity; and enhances the expression of anti-inflammatory IL-1RA and arginase. Our mechanism of action studies further demonstrate that furosemide reduces LPS-induced upregulation of endoplasmic reticulum (ER) stress marker genes, including Grp78, Atf4, Chop, tXbp1, and sXbp1. These data support the observation that furosemide is a known drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype, a potentially powerful and beneficial pharmacologic effect for inflammatory diseases such as AD.

    View details for DOI 10.1021/acschemneuro.0c00445

    View details for Web of Science ID 000600203100018

    View details for PubMedID 33225679

  • Is Inhaled Furosemide a Potential Therapeutic for COVID-19? AMERICAN JOURNAL OF THE MEDICAL SCIENCES Brennecke, A., Villar, L., Wang, Z., Doyle, L. M., Meek, A., Reed, M., Barden, C., Weaver, D. F. 2020; 360 (3): 216-221

    Abstract

    The potentially lethal infection caused by the novel Severe Acute Respiratory Disease Coronavirus-2 (SARS-CoV-2) has evolved into a global crisis. Following the initial viral infection is the host inflammatory response that frequently results in excessive secretion of inflammatory cytokines (e.g., IL-6 and TNFα), developing into a self-targeting, toxic "cytokine storm" causing critical pulmonary tissue damage. The need for a therapeutic that is available immediately is growing daily but the de novo development of a vaccine may take years. Therefore, repurposing of approved drugs offers a promising approach to address this urgent need. Inhaled furosemide, a small molecule capable of inhibiting IL-6 and TNFα, may be an agent capable of treating the Coronavirus Disease 2019 cytokine storm in both resource-rich and developing countries. Furosemide is a "repurpose-able" small molecule therapeutics, that is safe, easily synthesized, handled, and stored, and is available in reasonable quantities worldwide.

    View details for Web of Science ID 000564335400004

    View details for PubMedID 32622469

    View details for PubMedCentralID PMC7833957

  • Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide PEERJ Wang, Z., Wang, Y., Vilekar, P., Yang, S., Gupta, M., Oh, M., Meek, A., Doyle, L., Villar, L., Brennecke, A., Liyanage, I., Reed, M., Barden, C., Weaver, D. F. 2020; 8: e9533

    Abstract

    The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.

    View details for DOI 10.7717/peerj.9533

    View details for Web of Science ID 000545868100011

    View details for PubMedID 32704455

    View details for PubMedCentralID PMC7350920

  • Biaryls from Anilines and Aryl Sulfoxides through Sigmatropic Rearrangement Synfacts Snieckus, V., Wang, Z., Weaver, D. 2020; 16 (2)

    View details for DOI 10.1055/s-0039-1691629

  • Brønsted Acid Catalyzed Synthesis of α-(3-Indolyl) Ketones Synfacts Snieckus, V., Wang, Z., Weaver, D. 2019; 15 (10)

    View details for DOI 10.1055/s-0039-1690982

  • A study on the impact of SO2 on CO2 injectivity for CO2 storage in a Canadian saline aquifer APPLIED ENERGY Wang, Z., Wang, J., Lan, C., He, I., Ko, V., Ryan, D., Wigston, A. 2016; 184: 329-336
  • A study of the effect of impurities on CO2 storage capacity in geological formations INTERNATIONAL JOURNAL OF GREENHOUSE GAS CONTROL Wang, J., Wang, Z., Ryan, D., Lan, C. 2015; 42: 132-137