Research

The focus of our research program falls into two broad and complementary areas:

1. Reaction and catalyst design and discovery

2017 Research Fig 1 Bifunct cat

One of our primary objectives is the development of new synthetic reactions, with a focus on the design and preparation of multifunctional catalysts that can facilitate important asymmetric bond formations. Our inspiration for these catalysts stems in part from the structure and function of Nature’s catalysts—enzymes. Nature uses a limited number of building blocks (20 amino acids) connected by a single type of bond (amide bonds), along with a trial-and-error approach (evolution), to furnish catalysts for certain reactions which typically possess outstanding activity and selectivity. Can we rationally design multifunctional catalysts with comparable utility to enzymes using any available building blocks (natural or unnatural), connected together with any of the vast array of synthetic reactions at our disposal? Currently, we are preparing catalytic systems that contain both organocatalytic and transition metal-based functionality, and we are exploring their application in important reactions for which there is a significant unmet need, including aldol reactions (figure) and additions to unactivated alkenes and alkynes. Our new reactions and catalysts may enable the efficient preparation of important bioactive compounds, including new anticancer and antibiotic natural product analogs.

2. Chemical probe discovery applied to important problems in biology and medicine

 

 

2017 Research Fig 1 Nat products

Our second focus is the preparation of molecules that can act as probes for the elucidation of important biological processes. As with our catalysis studies, our work in this area draws significant inspiration from Nature—in this case small molecule natural products. We often utilize the strategy of function-oriented synthesis (FOS, a term coined by Prof. Paul Wender), a version of the pharmacophore concept widely utilized in medicinal chemistry, to design and prepare bioactive compounds. In this approach, “lead” molecules, primarily complex natural products, are modified to provide target compounds that are more synthetically accessible while still retaining (or even improving) the desired bioactivities. These modifications can also provide access to more diverse compounds with improved medicinal properties. We are striving to answer the question: Can we more generally and efficiently utilize the structural leads provided by Nature for drug discovery? Natural products have evolved in response to pressures that are often irrelevant to human disease, and our research strives to identify structural features of natural products that can be replaced or “swapped out” with scaffolds and building blocks that have fewer liabilities.

Presently, our main project in this area is the synthesis of simplified analogs of the antifungal agent sordarin, a compound which inhibits fungal protein synthesis by selective binding to fungal eurkaryotic Elongation Factor 2 (eEF2). Systemic fungal infections kill thousands of immunocompromised patients every year, and new antifungal drugs are urgently needed. Semi-synthetic derivatives of sordarin were previously under intensive investigation by the pharmaceutical industry, but did not ultimately reach clinical stages. We have designed novel analogs to address specific liabilities of this compound class, and are utilizing an innovative synthetic approach to prepare structurally diverse compounds not accessible via semi-synthesis from the natural product.

Voltage-gated potassium channels are essential for the transmission of electrical signals along nerve cells. Aberrant activity of ion channels is linked to a wide range of disorders and diseases; for example, inhibition of Kv1.5 is being investigated for the treatment of atrial arrhythmia. The vast majority of ion channel inhibitors (including nerve toxins) act by blocking the central pore of the channel; in collaboration with the Sack Lab (UC-Davis Dept. of Physiology and Membrane Biology), we are building and studying analogs of the snail toxin natural product BrMT that attenuate channel activity without blocking the central pore.

Generic bivalent ligand figure cropped

Another central strategy that we utilize for the discovery of valuable bioactive compounds is multivalency. Related to our multifunctional catalyst approach, we combine ligands for different cell surface proteins in order to target specific combinations of proteins (usually receptors) which may mediate unique and disease-relevant signaling that differs from the signaling of the monomeric receptors (figure). This strategy was first pursued decades ago by Prof. Phil Portoghese, but it remains an underutilized but highly promising approach for the elucidation of complex signaling pathways that underpin biology. After several years of foundational efforts, we will be excited to disclose our early work in this area for the first time in 2017. Our work in this area is performed in collaboration with Dr. Hartmut Weiler at the Blood Research Institute.

2017 Research Fig 4 ML161

Protease-activated receptors (PARs) are G-protein coupled receptors (GPCRs) that have “built-in” ligands that become activated upon cleavage of the N-terminus of the receptor by specific proteases, including thrombin. PARs mediate important signals for processes that include platelet activation (blood clotting) and inflammation (response to infection). Inhibitors or activators of PARs could be used to prevent or treat heart attack and stroke, the leading cause of death worldwide; we are also investigating their use in the treatment of sepsis, restenosis (re-narrowing of arteries after a vascular procedure such as stent implantation), and prevention of cancer cell metastasis. In collaboration with the Flaumenhaft Lab (Beth Israel Deaconess Medical Center/Harvard Medical School), we are studying compounds we discovered called parmodulins, including ML161 (parmodulin 2), our lead compound that inhibits PAR1 via a unique mechanism that could offer a better safety profile for future patients with cardiovascular disease and sepsis. Our compounds are also under investigation by Dr. Berend Isermann (Otto-von-Guericke-Universität Magdeburg) as cytoprotective agents to limit damage from e.g. myocardial infarction.

Our efforts depend on the tools and techniques of synthetic and medicinal chemistry to efficiently prepare the desired catalysts and bioactive molecules. In many cases, it is advantageous to create or improve synthetic methods to gain access to valuable structural patterns that are new or underexplored. Molecular modeling approaches are also utilized to help prioritize possible catalysts and ligands. Catalysts are optimized to improve activity, selectivity, substrate scope, and stability, while potential probes are optimized to improve parameters such as potency, solubility, permeability, and metabolic stability, in order to expand their utility for in vivo studies.