Rampant proteolysis at the intersection of therapy-induced hypoalbuminemia and acute pancreatitis

Protease inhibition is the intended mechanism of action for drugs across a broad range of diseases: cancer, cardiovascular and stroke, diabetes mellitus, macular degeneration and Alzheimer’s. Treatment for fungal and multiple viral infections, including Sars-Cov-2, also relies upon inhibition of pathogen-specific proteases. This work examines the non-therapeutic proteolytic activity of one such drug, nelfinavir (tradename VIRACEPT™), approved as an inhibitor of HIV protease, the largest, “biotech launch” in history at the time of its introduction. Methods are described in the companion manuscript [Leonard et al. (2022), 4open 5, 11]. These methods are not only suitable for examination of on-target activity but also of off-target activity. Herein, it is demonstrated that nelfinavir is active both as an inhibitor and as a promoter of proteolysis of key blood proteins. Observations are readily connected to known drug induction of acute pancreatitis and attendant hypoalbuminemia. The benefits of expanding molecular-level, early-stage, off-target/off-substrate activity drug candidate evaluation become apparent. Finally, the reality of drug-induced disease places new demands on existing clinical procedures, namely that side effects be approached as symptoms of an induced disease.