Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Abstract

Leflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH is a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step in the de novo synthesis of the pyrimidine nucleotides. LF produces cellular depletion of pyrimidine nucleotides required for cell growth and proliferation. Based on the affected cells the outcome can be attainable as immunosuppression, antiproliferative, and/or the recently gained attention of the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is an additional mechanistic benefit of LF, which inhibits immunological events such as cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is approved for the treatment of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been used off-label for the treatment of relapsing-remitting multiple sclerosis. However, LF antiviral activity is repurposed and under investigation with related compounds under a phase-I trial as a SARS CoV-2 antiviral in cases with COVID-19. Despite success in improving patients’ mobility and reducing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF should not be used in patients with hepatic impairment or in combination with drugs elaborating a burden on the liver without regular monitoring of liver enzymes and serum bilirubin as safety biomarkers. This study aims to review the pharmacological and safety profile of LF with a focus on the LF-induced hepatic injury from the perspective of pathophysiology and possible protective agents.

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

“…DHODH inhibitors (DHODHi) have been used to treat malignant tumors, autoimmune diseases, viral or bacterial infections, parasitic diseases, and other diseases [ 23 , 31 , 33 , 34 , 35 ]. DHODHi inhibit viral infection by three mechanisms: (1) inhibiting viral replication (pathway 1 in Figure 2 ), (2) promoting interferon-stimulated genes (ISGs) expression (pathway 2 in Figure 2 ), and (3) regulating inflammation (pathway 3 in Figure 2 ).…”

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment

“…Exogenous uridine (100 μM) supplementation significantly decreased the proliferation inhibitory rate to 3.3, 6.2, 17.1, and 21.3%, respectively, suggesting that exogenous uridine predominantly rescued proliferation inhibition induced by compound 13t . Furthermore, previous studies revealed that teriflunomide also exhibited inhibitory activities against several human protein kinases, such as EGFR, JAK1, and JAK3. − Therefore, we evaluated the inhibitory activities of 13t (10 μM) against 98 human protein kinases that are commonly activated in human malignancies including EGFR, JAK1, and JAK3. The results showed that 13t at a high concentration of 10 μM only affected the protein kinases activity very slightly with most of the inhibitory rate lower than 30% (Table S1), suggesting that 13t did not affect the kinases activity.…”

Cell-Based Double-Screening Method to Identify a Reliable Candidate for Osteogenesis-Targeting Compounds

“…Lef is a malononitrile derivative that inhibits dihydroorotate dehydrogenase and several protein tyrosine kinases [ 43 , 44 ]. Although Lef is an immunomodulatory agent used to treat rheumatoid arthritis [ 45 ], there have been no studies on the effects of Lef on osteoblastic differentiation. Malviya et al reported that 15 µM Lef inhibited the proliferation of primary human osteoblasts [ 46 ].…”