Simplepath IIB: pre-clinical development of cannabinoid analogs

The National Institute of General Medical Sciences awarded Invizyne Technologies, Inc. (a division of Exozymes, Inc.) $1,034,289 on July 1, 2026, to develop SIMPLEPATH IIB, a pre-clinical research platform for producing a library of cannabinoid analogs through a cell-free enzymatic system.

The project focuses on synthesizing common, rare, and novel cannabinoid analogs using a 7-enzyme system that transforms low-cost inputs into cannabigerolic acid and related compounds. The library will be screened for binding affinity to CB1, CB2, and NAV1.8 receptors to identify lead compounds for further pre-IND development. Target therapeutic applications include glaucoma, inflammatory bowel disease, Huntington's disease, obesity, and chronic pain. The cell-free manufacturing approach addresses significant barriers to cannabinoid drug development—specifically the lack of scalable access to diverse analogs for rapid screening and the production challenges of plant-derived or engineered microbial systems.

Invizyne is a small disadvantaged business based in Monrovia, California. The award operates under CFDA 93.859 (Biomedical Research and Research Training), with performance occurring in Monrovia, California. The period of performance runs from July 1, 2026 through June 30, 2028.

Abstract

Prenylated resorcyclic acids (e.g. cannabinoids, cbxs) are bioactive natural products based on a privileged resorcylic acid chemical scaffold that display current and potential therapeutic uses. While some cbxs are highly abundant in plants (e.g. thca/cbda) and therefore well studied, many low abundant (rare) cbxs from plants (e.g. cannabigerolic acid (cbga) and "varins" cannabidivarinic acid (cbdva) and tetrahydrocannabivarinic acid (thcva)) have potential therapeutic use. Production of cbxs in plants, particularly rare cbxs, is problematic due to crop variability and purification challenges. Considerable effort to develop alternative methods to produce common and rare cbxs in engineered microbes also faces challenges such as low titer and lack of modularity limiting fast and cost-effective production of CBX analogs that can be screened for activity relationships against relevant receptors (e.g. CB1/CB2). Invizyne technologies is developing an alternative, cell-free method to produce common, rare, and new-to-nature cbxs (e.g. CBX analogs) using enzymatic transformations. Rare cbxs and their analogs have demonstrated bioactivity and show promise to treat numerous indications such as glaucoma, inflammatory bowel disease, huntington's disease, obesity, and chronic pain among other central nervous system indications. Our primary focus is development of a library of cbxs based on the resorcyclic acid core scaffold that will be screened for binding to CB1, CB2, or NAV1.8 receptors and then quickly scaled to enable further pre-IND studies. A key barrier to developing CBX drugs has been access to diverse analogs for screening that can also be scaled quickly once hits are identified. In a major development, invizyne has developed a 7-enzyme system for the production of cbga and other CBX analogs from low cost inputs, that we call simplepath. Initial phase i and II results yielded titers of multiple common, rare, and new- to-nature pras at titers between 5 and 25 g/l, exceeding cell-based methods by several orders of magnitude while also demonstrating the modularity of the system and its relevance for further commercial development, especially as IT relates to CBX drug development. Our goal in this phase IIB application is to expand our simplepath approach is to screen the CBX analogs produced for binding to CB1, CB2, or NAV1.8 receptors in various binding modes while broadening structural diversity to bridge the GAP from drug discovery to pre-clinical validation. Phase IIB work is necessary not only to identify lead CBX analogs for further clinical development but to establish a consistent, highly pure supply of a range of cbxs to be used as therapeutics or nutraceuticals at costs that compete with or surpass microbial and plant derived CBX production.