Projects Overview

CXCR4

The CXCR4 project is a multifaceted program focusing on developing small molecules for therapeutic intervention in a number of diseases including cancer, stem cell transplant, neutropenia and HIV infection. The biological roles of this G-protein coupled receptor (GPCR) are both far reaching and significant. The main process that this receptor regulates is one on a cellular level termed chemotaxis, which is the movement of cells within the human body. These include regulation of immune cells, propagation of cancer cells, and facilitating HIV entry. Furthermore, since this receptor involves controlling cell location, it can be coupled together with other therapies to enhance therapeutic effects. THE LRG has developed CXCR4 antagonists that can be administered orally and are therapeutically effective in a number of mouse models representing various disease states.

NMDA Receptor Antagonist and Potentiators

The NMDA receptor is critical for nearly every function of the brain and is involved in learning, memory, brain development and synaptic plasticity. NMDA receptor dysfunction has been implicated in numerous neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, schizophrenia and depression. Over a decade ago, the Liotta and Traynelis Research Groups started their drug discovery endeavor in the NMDA receptor (NMDAR) field. Multiple series of subunit-selective NMDAR modulators were identified by a high-throughput screening study. Subsequent medicinal chemistry campaigns were carried out in the Liotta Research Group to explore the structure-activity relationship in each series of NMDAR modulators.

CBD/THC Prodrugs

In the Liotta Research Group, we propose to apply our substantial experience with prodrug synthetic strategies to develop a novel CBD prodrug that is water soluble, allows for conventional formulation, improves oral bioavailability, and modifies tissue distribution in a favorable manner. This prodrug will be able to more predictably and effectively treat intractable epilepsies that are currently treated with Epidiolex®, as well as treat developmental epileptic encephalopathy (DEE), which qualifies for orphan drug status. Our approach makes use of dual-functional moieties with controlled cleavage mechanisms placed onto the phenolic hydroxyls of CBD, to create structurally novel CBD prodrugs which are highly soluble and orally bioavailable. This is achieved through careful selection and design of a solubilizing, circulating linker and attachment group.

Neurosteroids and Lipid Prodrugs

Neurosteroids are a class of endogenous steroids synthesized within the central nervous system to modulate neuronal activity and function. Neurosteroids play critical roles in cognition, mood regulation, stress response, and neuroprotection, influencing synaptic transmission and neurotransmitter release to impact brain function and behavior profoundly. Progesterone, allopregnanolone, and dehydroepiandrosterone (DHEA) have shown promise in preclinical studies for their neuroprotective effects in conditions such as traumatic brain injury (TBI), stroke, and neurodegenerative diseases. Recent advancements in clinical development have led to FDA approvals for brexanolone (Zulresso) and ganaxolone (Ztalmy®), marking significant milestones in neurosteroid-based therapy. However, challenges such as poor solubility and complex pharmacokinetics hinder their efficacy. Our ongoing research focuses on synthesizing C20-oxime-based prodrugs for neurosteroids to enhance solubility and bioavailability while maintaining therapeutic efficacy. We aim to overcome these limitations through pH-sensitive self-immolation prodrug linkers (Figure 1), enabling the effective delivery of neurosteroids for improved neurological and psychiatric outcomes.

Lipid Prodrugs

Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of tenofovir (TFV) that form a major component of most prophylactic and therapeutic regimens for the treatment of HIV-1 globally. However, TDF is rapidly cleaved in plasma and in the liver by esterases to generate systemic TFV, which accumulates in the kidney, causing nephrotoxicity over the course of chronic treatment. The release of TFV in plasma has also been linked to bone mineral density depletion. Although TFV plasma exposure is dramatically reduced with TAF relative to TDF, a large percentage of TAF is extracted by the liver due to cleavage by carboxylesterase 1. As a result, only small fraction of TAF is available to access target HIV infected cells.