Sinha Laboratory | Helen & Robert Appel Alzheimer’s Disease Research Institute

Sinha laboratory focuses on development and optimization of brain permeable lead compounds as tool candidates and therapies for Neurodegenerative diseases, including Alzheimer’s disease (AD). Sinha lab also specializes in developing prodrug approaches to improve the selectivity and accessibility to the brain. Beyond amyloid hypothesis, human genetics and mechanistic studies revealed exciting disease-associated target proteins that remain largely unexplored. Working with other labs at Appel Institute, Sinha laboratory aims to identify and develop hit to lead candidates for some of these target proteins restoring function in microglia, astroglia, and synaptic function. Hit candidates will be identified by classical and virtual high throughput screening (HTS) assays, and Medicinal Chemistry is performed for the lead discovery.

Associated Lab Members

Lab Achievements

1) Developed and evaluated chemically programmed antibody strategy, antibody-drug conjugates and prodrugs of anticancer agents that improve pharmacokinetic properties and selectivity of small molecules. These studies were funded through NCI.

2) Developed antibody-catalyzed reactions and prepared numerous naturally occurring compounds, including acetogenins and epothilones. Acetogenins are potent Complex I inhibitors and epothilones are anticancer agents.

3) Prepared and examined Gleevec and DV2-103 analogs that potently inhibit Amyloid-b (Ab) production in cell culture and works synergistically when combined with a b secretase inhibitor. In addition, natural product extracts were screened to identify a g secretase inhibitor, and brain-permeable amide prodrugs of the FDA approved Transthyretin stabilizer, Tafamidis, were developed to target and stabilize the protein in brain. These studies were funded through the JPB foundation.

4) Inhibitors of CK1 autophosphorylation were developed to selectively increase PS1-Ser367 phosphorylation that was earlier shown to reduce Ab load in brain through inducing autophagy. These studies were funded through the JPB foundation and Cure Alzheimer’s fund.

Lab Projects

vHTS strategy

We have performed Ligand based virtual HTS to identify compounds in two database containing 3.2 million commercially available synthetic compounds and 1.2 billion hypothetical compounds that can be obtained commercially through synthesis on demand with high confidence and identified over 1000 top scoring small molecules. We aim to screen and evaluate these small molecules to identify potent hit and lead compounds for a microglia target and perform Medicinal Chemistry for lead development and optimization.

Prodrugs of CNS active compounds

The goal of this study is to develop and utilize prodrug approach for selective and effective delivery of CNS active drugs to targets of interest in brain. CNS drug delivery has remained a major challenge especially for those possessing greater than 400Da molecular weight. Prodrugs are inactive derivatives of a drug and that undergo biotransformation to release active drug. Brain permeable and nontoxic inactive prodrugs are desirable. Prodrug approach aims to overcome the physicochemical and pharmacokinetic barrier of a pharmacologically active compound found restricting the brain exposure of such molecules. We are currently developing prodrugs of cGAS and STING inhibitors.

CD33 inhibitors

In this study, we will investigate and examine the possibility of CD33 inhibition using small molecules. It is well established that high expression of CD33 protein, which is sialic acid (SA)-binding immunoglobulin-type lectin (Siglec) protein, in microglia adversely affects the latter’s ability to cause phagocytosis and clearance of neurotoxic Ab peptide and tau protein deposits in brain. This study will be funded through Cure Alzheimer’s fund.

Other studies of interest

Include identification and development of inhibitors of tau aggregation and propagation, inhibitors of tau and APOE expression, senolytics, and autophagy inducers. One of the natural product derivatives earlier evaluated in Sinha laboratory was found to reduce tau expression in 3D culture assay, while several synthetic small molecules appears potent senolytics or autophagy inducers.