4.7. Leflunomide (Arava)
It is a synthetic, small molecule and an isoxazole-carboxamide derivative (Figure 8B). It was approved by the U.S. FDA in 1998 for the oral treatment of rheumatoid arthritis [173,174,175]. It is also used off-label as a replacement therapy in kidney transplant recipients with polyomavirus BK [176] and for cytomegalovirus disease in transplant recipients resistant to standard antivirals [177]. Mechanistically, it is a disease-modifying agent with anti-inflammatory and antiproliferative effects. It inhibits pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, an important enzyme in the de novo synthesis of uridine monophosphate [178]. Leflunomide is a prodrug and the active metabolite (isoxazole ring is open: teriflunomide (Aubagio)) is responsible for its activity [179]. It inhibits rapidly dividing cells such as activated T cells. It has also been found to block the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes. The drug inhibits the replication of cytomegalovirus, herpes simplex virus 1, and polyomavirus BK by interfering with nucleocapsid tegumentation and virion assembly [179]. Given the above activities, a high dose of leflunomide is being evaluated for the treatment of ambulatory patients with mild COVID-19 at the University of Chicago Medicine (NCT04361214; n = 20).