Antiviral activity of the compound described by the current invention has been established against multi-protease inhibitor-resistant HIV-1 variants and demonstrated effective in patients with widespread resistance to current protease inhibitors.

Drug-resistance is a critical factor contributing to the loss of clinical benefit of currently available human immunodeficiency virus-1 (HIV-1) therapies. Accordingly, combination therapies have evolved to address the rapidly evolving virus. However, there has been great concern regarding the growing resistance of HIV-1 strains to current therapies as multi-drug resistance to protease inhibitors is becoming more common. The current technology embodies a breakthrough against this immense obstacle of existing HIV-1 treatments. Compositions and methods of inhibiting the protease of multi- drug resistant retroviruses such as HIV-1 are available for non- exclusive licensing and commercial development. The antiviral activity of the compound described by the current invention has been established against multi-protease inhibitor-resistant HIV-1 variants and demonstrated effective in patients with widespread resistance to currently available protease inhibitors. In addition, commercial development of this composition has resulted in the production of a novel drug that has recently been granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 in patients who are non- responsive to existing antiretroviral therapies. The available composition retains the unique ability to inhibit drug resistant mutants due to its distinctive points of interaction with the enzyme: the agent tightly binds to the part of the protease substrate binding site, which the virus cannot easily change. Other "conventional" protease inhibitors bind to other parts of the protease substrate binding site, which the virus can relatively easily change, rendering these drugs ineffective after repeated use. Therefore, the current technology represents a highly effective method of targeting drug resistant HIV-1 strains. Applications: (1) Novel therapeutics for the treatment of drug- resistant HIV; (2) Safe and effective methods for administration of anti-HIV/AIDS drugs Development Status: Clinical trials have been performed with Prezista(TM) (darunavir), a drug resulting from development of the present technology, which has received accelerated approval from the FDA. Related Publications: 1. K Yoshimura, R Kato, MF Kavlick, A Nguyen, V Maroun, K Maeda, KA Hussain, AK Ghosh, SV Gulnik, JW Erickson, H Mitsuya. A potent human immunodeficiency virus type 1 protease Inhibitor, UIC-94003 (TMC 126), and selection of a novel (A28S) mutation in the protease active site. J Virol. 2002 Feb;76(3):1349- 1358. 2. Y Koh, K Maeda, H Ogata, G Bilcer, T Devasamudram, JF Kincaid, P Boross, Y-F Wang, Y Tie, P Volarath, L Gaddis, JM Louis, RW Harrison, IT Weber, AK Ghosh, H Mitsuya. Novel bis tetrahydrofuranyl-urethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) potent against multi-PI- resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 2003 Oct;47(10):3123-3129. 3. AK Ghosh, PR Sridhar, S Leshchenko, AK Hussain, J Li, AY Kovalevsky, DE Walters, JE Wedekind, V Grum-Tokars, D Das, H Mitsuya. Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance. J Med Chem. 2006 Aug 24; 49(17):5252-5261. 4. AK Ghosh, P Ramu Sridhar, N Kumaragurubaran, Y Koh, IT Weber, H Mitsuya. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance. ChemMedChem. 2006 Sep;1(9):939- 950.

U.S. Patent Application No. 09/720,276 filed 07 Mar 2001 (HHS Reference No. E-200-1998/0-US-02) European Patent Application No. 99931861.1 filed 23 Jun 1999 (HHS Reference No. E-200-1998/0-EP 08) Inventors: John W. Erickson (SAIC/NCI), Sergei V. Gulnik (SAIC/NCI), Hiroaki C. Mitsuya (NCI), and Arun K. Ghosh

Licensees Sought: Available for non-exclusive licensing.