Posters

The One-Stop Metabolite Shop: Employing Multiple Tools to Solve Challenging Metabolite Projects

The one-stop metabolite shop: employing multiple tools to solve challenging metabolite projects

Presented at: DMDG virtual meeting January 2021

Often several strategies are needed to access all key metabolites observed during drug development programs. Hypha has developed a “one-stop metabolite shop” scheme, which utilizes a combination of biological and chemical techniques in order to fulfil requirements to access any type of metabolites.

The one-stop metabolite concept offers a parallel or sequential screening step to identify the most productive and cost-effective method to produce target metabolites.  Depending on the type and quantity of metabolite required, a combination of chemical synthesis, mammalian S9, microbial biotransformation and recombinant phase I enzymes can be employed. Once the optimal production system is identified, the method can be scaled up to provide up to tens of grams of purified metabolites.

Recently introduced to this suite of techniques are an extended panel of PolyCYPs® enzymes, microbial CYPs cloned from some of Hypha’s actinomycete strains and expressed in E. coli together with redox partners. These enzymes are effective for scalable synthesis of CYP-derived human and other mammalian metabolites.

For glucuronides, a proprietary late-stage chemical screen has been devised, consisting of multiple robust conditions with deprotection strategies suitable for acyl glucuronides and some unstable N-glucuronides. The chemical screen has proven effective for producing at least one glucuronide from 90% of a panel of commercially available drugs from which glucuronides are known to be formed.

The synergy of using the one-stop shop concept to access sets of metabolites will be exemplified using recent case studies.

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