Promise and limits of cyclodextrins as drug delivery systems for MEDS433

COVID-19 has cast light on our general unpreparedness to tackle virus pandemics, a scenario similar to the effect of the terroristic use of a category C biological warfare agent. The human dihydroorotate dehydrogenase (hDHODH) inhibitors targeting the host’s pyrimidine synthesis pathway emerged as new inhibitors of virus replication.1 2-hydroxy-N-(2,3,5,6-tetrafluoro- [1,1'- biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (MEDS433), developed at Turin University emerged as best-in-class hDHODH inhibitor (IC50 = 1.2 nM) and preliminary data showed its ability to inhibit the in vitro SARS-CoV-2 replication (EC50 = 0.063 μM) with an excellent safety profile (SI >7900). In 2022, the development of MEDS433 water-soluble formulations was granted by NATO SPS Programme through the VIPER project. Three different cyclodextrins, sulfobutylether-beta-cyclodextrins (SBE) 2-hydroxypropyl-beta- cyclodextrin (HP), heptakis(2-O-oligo(ethylene oxide)-6-hexylthio)-beta-CD (SC6OH) were investigated for the preparation of water-soluble MEDS433 complexes. Taking into account the primary outcomes of the VIPER project, herein we discuss the promise and limits of cyclodextrins as drug delivery systems for MEDS433.