In our last newsletter of the year we look at the need for accessing glucuronides and share hot off the press news about a new UGT kit that will be available in Q1 2025.
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Hypha Discovery
What's New Q4 2024
Focus Features
NEW UGT kits
Our scientists have been successful in cloning and purifying a set of microbially-derived UGT enzymes. The enzymes - PolyUGTsTM - are able to glucuronidate a variety of drugs and agrochemicals.
New for Q1 2025 will be a kit form of PolyUGTs for clients to use in their own labs to make glucuronides for MetID and further testing. Both screening and scale-up kits will be available. These complement our existing PolyCYPs+ kits used for making CYP-derived and other phase I metabolites.
O-glucuronides of ezetimibe are produced by several isoforms in Hypha's PolyUGTs screening kit. In the example above, the highest yielding enzyme PolyUGT 179 was scaled up using a UDPGA cofactor-providing Streptomyces host into which the UGT had been cloned. Two O-glucuronides of ezetimibe were purified and the structures confirmed by NMR spectroscopy, reflecting what was observed in HLM incubations.
Ezetimibe phenoxy glucuronide is unusual in that it is pharmacologically active and is more potent at inhibiting cholesterol absorption in the gut than the parent drug. Repeated enterohepatic circulation results in a long duration of action.
The need for glucuronides
Despite acyl glucuronide being the only glucuronide type specifically mentioned in the FDA’s MIST guidance as a potential metabolite type of concern, all types of glucuronides are needed by clients for DDI studies or as analytical standards. In fact glucuronides constitute at least a third of the metabolites we make according to a recent internal analysis. Of these, 15% were acyl glucuronides, 49% O-glucuronides and 36% N-glucuronides.
The need for glucuronide metabolites of clinical stage drugs reflects the inclusion of moieties susceptible to glucuronidation at the drug design stage. For example, nitrogen-containing ring systems such as pyrazoles, triazoles and tetrazoles are more resistant to oxidative metabolism but can be more susceptible to N-glucuronidation.
Latest blog post
Major biotransformation routes of aficamten involving hydroxylation, onwards glucuronidation and gut metabolism
Hypertrophic cardiomyopathy is a surprisingly common genetic heart disease, affecting 1:200 to 1:500 people in the US. Aficamten is a cardiac myosin inhibitor currently in phase 3 clinical development to treat this inherited disorder. Our latest blog article looks at the routes of biotransformation of aficamten, a drug mainly eliminated by metabolism.
Highlights include:
- Major CYP-mediated hydroxylated diastereomers
- Onwards glucuronidation to a major metabolite
- Involvement of gut microbes to form a major fecal metabolite
- Important aspects of oxadiazole gut metabolism
Recent paper picks
Major circulating glucuronides of icenticaftor
This paper from scientists at Novartis describes the human ADME characteristics of icenticaftor and its major circulating direct and indirect glucuronides. Several interesting elements are discussed in the paper and highlighted here.
Discovery of unprecedented human stercobilin conjugates of inavolisib
Highlighted in this paper are novel metabolites of inavolisib conjugated with part structures of stercobilin, a microbial metabolite of bilirubin found in the gut. To our knowledge this type of drug conjugate has not been reported before now.
Stay tuned
If you're interested in keeping up with what's happening at Hypha Discovery, our blogs and paper picks, follow us on LinkedIn for regular updates.
Metabolite Tales blog
Have a look at our other blog articles we've published so far here.
