Drug Discovery & Translational Research

Parkin Agonist Development

I collaborated with chemical biologists to identify small-molecule activators of Parkin. In dopaminergic neurons, Parkin agonists enhanced mitophagy, improved survival, and protected against α-synuclein–induced degeneration. I also demonstrated that Parkin loss shifts cell fate toward glial lineages, linking target perturbation to lineage-state biomarkers for translational stratification.

I generated oncology-facing rationale integrating observations that PARK2 downregulation is common across cancers with cell-based efficacy readouts. Manuscript under review, Nature.

TAC & Lysosomal Rescue

I evaluated a Telomerase Activating Compound (TAC) designed to enhance neuronal resilience by targeting mitochondrial and lysosomal biology. In iPSC-derived neurons, TAC reduced α-synuclein pathology, restored integrated stress response markers (ATF4/ATF3), and decreased senescence-associated phenotypes.

In parallel, I demonstrated that Perillaldehyde (PAH) rescues lysosomal function in the dual-hit model, restoring LAMP1, LAMP2, NRF2, and TFEB protein levels while progressively clearing α-synuclein inclusions over 8 days. Western blot pharmacodynamic profiling confirmed reduction of both total and phosphorylated α-synuclein, decreased HDAC6 (aggresome marker), and normalized autophagy-lysosomal pathway proteins — providing a multi-readout therapeutic validation dataset. Published in Bayati et al., Nature Neuroscience 2024.

Perillaldehyde (PAH) treatment timeline and confocal time course. PAH rescues lysosomal function and progressively reduces α-synuclein inclusion burden over 8 days in iPSC-derived DA neurons treated with the dual-hit protocol. Left panels show treatment scheme; right panels show confocal imaging at Day 1, 4, and 8 demonstrating inclusion clearance versus no-treatment control. Bayati et al., Nature Neuroscience 2024.

Western blot pharmacodynamic panel: PAH treatment restores LAMP1, LAMP2, TFEB, and NRF2 protein levels while reducing α-synuclein and phospho-α-synuclein (S129) in dual-hit DA neurons. HDAC6 (aggresome marker) decreases with treatment, confirming dissolution of insoluble aggregates. Multi-readout biomarker validation of lysosomal rescue as therapeutic mechanism. Bayati et al., Nature Neuroscience 2024.

Host-Directed Antiviral Strategies

My first-author JBC 2021 paper (Editors' Pick) was the first to demonstrate that SARS-CoV-2 enters cells via clathrin-mediated endocytosis — Spike protein binds ACE2 and is rapidly internalized through CME. Building on this, I contributed to two drug-discovery programs: a PIKfyve chemical probe (IC50 = 0.82 nM) that blocks viral trafficking and replication (J. Med. Chem. 2022), and CSNK2 inhibitors that prevent Spike endocytosis across human, bat, and murine β-coronaviruses (ACS Chem. Biol. 2022). I translated these mechanisms into scalable screening platforms using Spike pseudovirus/GFP quantification on the Opera Phenix HCS system.

Mechanism of host-directed antiviral strategy: CSNK2 (Casein Kinase 2) inhibition blocks multiple stages of SARS-CoV-2 lifecycle — from Spike/ACE2 binding and clathrin-mediated endocytic entry, through viral replication, to cell-to-cell transmission. This host-kinase targeting approach provides broad-spectrum activity against β-coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV). Published in Yang, Dickmander, Bayati et al., ACS Chemical Biology 2022.

Structure-activity relationship (SAR) correlation between CSNK2A kinase inhibition potency and antiviral activity against β-coronaviruses. The strong correlation (R² = 0.68) across the pyrazolopyrimidine series validates CSNK2 as the mechanistic target for antiviral activity. 30 inhibitors were profiled using nanoBRET target engagement assays and MIV-nLuc reporter viral assays. Yang, Dickmander, Bayati et al., ACS Chemical Biology 2022.

Biomarker Strategy & Translational Execution

I develop and execute target engagement (TE) and pharmacodynamic (PD) biomarker strategies across iPSC-derived neuronal and epithelial systems. This integrates imaging biomarkers (protein aggregation burden, lysosomal stress, mitophagy flux), protein biomarkers (Western blot, ELISA/MSD/Luminex), nucleic acid readouts (RT-qPCR, ddPCR, RNA-seq), and mass spectrometry–guided proteomics from whole-cell and subcellular fractions.

I have applied LC-MS/MS workflows for small-molecule PK quantification (including FB231) and used proteomic discovery to prioritize candidate biomarkers, guiding downstream validation with orthogonal assays.

High-Content Screening & Hit Discovery

I translated the SARS-CoV-2 cellular entry mechanism into scalable cell-based screening assays using Spike pseudovirus and GFP quantification on Opera Phenix HCS. These platforms enabled hit discovery and validation of viral-entry inhibitors across dose-response and time-course designs in Caco-2, Calu-3, and Vero E6 cells.

Cytokine Profiling & Inflammatory Signaling

I profile neuroinflammatory cytokine signaling at RNA and protein levels using MSD/Luminex multiplex panels to quantify immune responses and link cytokine stress to aggregation, viability, and biomarker outputs. I also design cytokine-stimulated assay platforms to interrogate TYK2-mediated JAK/STAT signaling and neuroinflammation in iPSC-derived neurons and microglia.

Senescence, ROS & Mitochondrial Bioenergetics

I evaluate compounds targeting cellular aging by measuring reactive oxygen species (ROS/MitoSOX), senescence markers, and mitochondrial function. Assays include plate-based ROS quantification, mitochondrial membrane potential, and integration with TERT biology to assess long-term cellular fitness under stress conditions.

Analytical Characterization — HPLC & DLS

I perform orthogonal analytical characterization to support formulation development, compound purity assessment, and nanoparticle quality control. HPLC/UHPLC workflows are used for compound purity, stability monitoring, and retention-time–based identification. Dynamic light scattering (DLS) provides hydrodynamic diameter distributions and polydispersity indices for nanoparticle and EV formulations, supporting batch-to-batch consistency and release criteria.

HPLC purity profiling is performed during compound synthesis QC and at defined stability timepoints (T0, 1-week, 4-week, accelerated). DLS is integrated into the formulation pipeline for LNP and microsphere preparations, guiding size optimization for target tissue delivery. Batch-to-batch reproducibility is assessed through overlaid intensity-weighted distributions and Z-average trending.

Detailed Methodology & Techniques

Comprehensive descriptions of key experimental techniques, assay platforms, and analytical methods referenced throughout this page.