The novel protease inhibitor, Prezista™ (darunavir), has been granted accelerated approval by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus-1 (HIV-1) in patients who are nonresponsive to existing antiretroviral therapies. Prezista™ embodies a breakthrough in the struggle against the notorious obstacle of current HIV treatments: drug-resistance conferring mutations.
The antiviral activity of Prezista™ has been established against multi-protease inhibitor-resistant HIV-1 variants and demonstrated effective in patients with widespread resistance to the currently available protease inhibitors. Prezista™ is approved for use in combination with low-dose administration of ritonavir, which helps decrease the breakdown of Prezista™ in the body, thereby enhancing drug efficacy.
The enzyme HIV-1 protease facilitates the processing of essential HIV-1 structural proteins and is required for virus assembly. Prezista™ and other currently available protease inhibitors have been designed to compete with the protease substrate by binding to the enzyme's active site. However, Prezista™ retains the unique ability to inhibit drug-resistant mutants due to its distinctive points of interaction with the enzyme.
Prezista™ binds inside the protease substrate-binding site, a region of limited variability due to the highly specific nature of the protease-substrate interaction. Other protease inhibitors extend outside the substrate binding site to a location of high mutation rate, which renders these drugs ineffective after repeated use.
Darunavir, marketed as Prezista™, has its origins at the National Cancer Institute's (NCI) Frederick laboratories of Dr. John Erickson, who headed the Structural Biochemistry Program for the NCI contractor, Science Applications International Corp. (SAIC), and scientists at the University of Illinois-Chicago (UIC).
The inventors determined that darunavir had a unique HIV-resistance profile and immediately recognized its potential value treating drug-resistant HIV infections. A joint National Institutes of Health (NIH)-UIC patent application was filed through the NIH Office of Technology
Transfer (OTT) in 1999, describing analogs of darunavir and methods of their use.
Inventors on the original patent application include Drs. John Erickson and Sergei Gulnik (SAIC Frederick), Dr. Hiroaki Mitsuya (NCI), and Dr. Arun Ghosh (UIC). The NIH OTT facilitated the nonexclusive licensing of the Prezista™ precursor to Tibotec, Inc., the current manufacturer of the drug. Meanwhile, Dr. Erickson and several colleagues left SAIC and joined Tibotec.
While there, Dr. Erickson's group suggested several structural modifications to the original compound to enhance its drug-like properties. The current molecule Prezista™, which was specifically covered by the original NIH patent application, was eventually developed by Tibotec, a division of Ortho Biotech Products, L.P.
Presently, two randomized clinical studies have demonstrated Prezista'sTM safety and efficacy in lowering HIV-1 viral load in drug-resistant patients. Prezista™ has not been shown to completely eradicate HIV-1 in patients; however, the drug's commercial availability offers considerable hope for individuals who have developed or were initially infected with protease inhibitor-resistant HIV-1. Thus, Prezista's™ approval represents a significant turning point in HIV-1 therapy that will likely influence the development of new therapeutic agents that specifically target drug-resistant retroviruses.
