The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis

TLDR

Drug repurposing leverages the chemical diversity and safety profiles of existing drugs, especially for neglected tropical diseases, and is common in academic efforts due to lower time and resource requirements. The study presents ReFRAME, a 12,000‑compound open‑access drug repurposing library assembled from commercial databases and patent mining. The library was screened against Cryptosporidium spp., identifying two active compounds, and an open‑access portal was created to share hits. Screening of ReFRAME identified two compounds, VB‑201 and an ASP‑7962 analog, that are efficacious in animal models of Cryptosporidium infection at clinically relevant doses, and 12,000 compounds have been purchased or synthesized for screening.

Abstract

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.