Development of Small Molecule Therapeutics Specifically Targeting Members of the Bunyavirales Order

Fabrico Technology, Professor Kevin Dalby, the Johnson & Johnson Centennial Professor of Chemical Biology & Medicinal Chemistry, and Dr. Tamer Kaoud, Research Assistant Professor of Chemical Biology & Medicinal Chemistry, College of Pharmacy, the University of Texas at Austin (UT), have successfully met and exceeded the Phase I technical objectives as specified in the original Phase I solicitation. The UT Team generated pseudotyped lentiviral particles bearing Hantavirus (i.e., HTNV and ANDV) and Vesicular Stomatitis Virus (VSV, as a positive control) glycoproteins. These particles were then utilized in an infection cell-based assay to screen for triptan derivatives that prevented Hantavirus entry via endocytosis pathway inhibition in the mammalian HEK293T, A549, and Caco-2 cell lines demonstrating minimum toxicity. As a proof-of-concept, thePhase I studies showed that tested triptans are safe with minimum non-specific interactions and cytotoxicity. Building on this success, Fabrico Technology and the UT Team intend to continue to develop, research and optimize triptan derivatives that demonstrated the greatest efficacy in Phase I. In this Phase II program, Fabrico Technology and the UT Team intends to collaborate with Professor Bente and Dr. Cajimat of the Galveston National Laboratory at UTMB Galveston to provide and be responsible for the conducting of Hamster animal studies with live virus using the identified triptan inhibitors. The Fabrico Technology, UT, and UTMB team intends to meet all of the technical requirements specified in the original Phase II solicitation, including; investigating the mechanism of action using mammalian cell lines and patient-derived organoids, determining the appropriate dose using in-vivo PK/PD modeling in Hamsters and in-vitro ADME (absorption, distribution, metabolism, and excretion), and performing safety/toxicity and efficacy studies in the same animal model using live Andes hantavirus. Fabrico intends to pursue supplemental funding from the NIH Antiviral Program to expand the UT Austin development and UTMB animal studies.