Arun Ghosh used lessons from nature’s molecules to design potential anti-HIV agents. After designing, synthesizing, and testing hundreds of molecules, one of his creations is now helping tens of thousands of children and adults living with HIV infection.
Saquinavir became the first protease inhibitor (PI) to earn FDA approval in 1995. It cut down patients’ viral loads and brought up CD4+ T-cell counts; the combination slowed the progression of HIV infection. Saquinavir was soon co-credited for the rapid turnaround in America’s rising AIDS death toll—two years after its approval, annual AIDS deaths in the U.S. had fallen from 50,000 to 20,000.1 Although saquinavir could effectively manage HIV infection, it was susceptible to drug resistance and it displayed poor pharmacokinetic properties. The HIV virus mutates quickly, and mutations that prevent saquinavir from binding to the protease enzyme can appear with repeated use, allowing the virus to overcome the otherwise toxic drug. Saquinavir’s poor pharmacokinetic properties stem from its comparatively large size and peptide-like structure.2 When not co-administered with ritonavir booster, its oral bioavailability is only 4%.3
In 1998, Arun Ghosh had two decades of experience synthesizing natural products and PIs.4 His experiments with PIs at Merck Research Laboratories (1988–1994) had shown that cycloethers like tetrahydrofuran (THF) and bis-THF (green, below) could replace a sprawling peptide-like region of saquinavir (blue, above).5,6 The cycloethers reduced molecular weight and polar surface area; these changes were expected to improve pharmacokinetic properties. When bound to protease, Compound 1 and Compound 10 formed some of the same interactions that saquinavir does. The oxygens hydrogen-bond to HIV protease’s peptide backbone, while the hydrocarbon portions engages in van der Waals interactions with the hydrophobic binding pocket. Now a professor, Ghosh continued to investigate how cycloethers, such as those found in natural products like monensin A and gingkolide B, could be attached to existing PI structural templates to afford improved PIs. He aimed to invent PIs with better pharmacokinetic properties, less severe side effects, lower cost of synthesis, and more combativeness toward drug resistance.2
The spirocyclic system (red) in bacterial ionophore monensin A inspired the simplified spiro system (red) with rearranged oxygen atoms in Compound 14.2 The oxygens and their spatial configuration were critical: replacing the 5-membered ring’s oxygen with methylene or inverting stereochemistry at the spirocenter significantly worsened potency.7 Although Compound 14’s inhibitory potency versus isolated HIV protease was in the nanomolar range (Ki = 20 ± 3 nM), its potency in a cell-based viral replication and infection assay was two orders of magnitude weaker (ID50 = 2.4 µM).7
The fused bis-THF system (blue) of ginkgolide B featured in Ghosh’s previous work at Merck (e.g., Compound 10). UIC-94017 was created by combining bis-THF with the structural template of previously approved PI amprenavir. The resulting compound UIC-94017 was a marked improvement over Compound 14: its enzyme inhibitory potency was ten-fold greater (Ki = 2.1 nM) and its cellular potency was nearly a thousand-fold greater (ID50 = 4.5 nM).8 UIC-94017 potently inhibited the infection of cultured cells by a dozen different drug-resistant HIV strains. In the same assay, other PIs were ineffective at concentrations up to 5 μM. UIC-94017 was also active against multidrug-resistant HIV isolated from patients for whom no available PI would work.8
Ghosh has speculated that UIC-94017 remains active against mutant HIV protease because it forms extensive interactions with the peptide backbone (see below).9 The shape of the backbone is stable from wild-type to mutant enzymes, unlike the side chains of the amino acids that line the binding pocket.2
In addition to its activity against drug-resistant HIV, UIC-94017 has a high oral bioavailability and serum half-life when co-administered with ritonavir booster (82% and 15 hours, respectively).10 UIC-94017, or darunavir, was developed by Tibotec and earned FDA approval in 2006 for the management of HIV infection in children and adults. Darunavir is now a part of drug regimens for tens of thousands of treatment-naïve and treatment-experienced patients worldwide.11
Complex natural products monensin A and ginkgolide B inspired Ghosh’s design of new PIs, including a front-line therapy for HIV infection. The strategy of mimicking nature’s molecules continues to aid the discovery of new medicines.12
Please note that this is not medical advice or an endorsement.
1. Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, June 3, 2011, Vol. 60, No. 21. http://www.cdc.gov/mmwr/PDF/wk/mm6021.pdf
2. Bioorg. Med. Chem. 2007, 15, 7576–7580.
3. Invirase (saquinavir mesylate) FDA label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020628s034-021785s011lbl.pdf
4. https://www.chem.purdue.edu/ghosh/allpublications.htm (Accessed 12/11/2016)
5. Bioorg. Med. Chem. Lett. 1998, 8, 687–690. (Also see references therein)
6. J. Med. Chem. 1994, 37, 2506–2508.
7. Bioorg. Med. Chem. Lett. 1998, 8, 979–982.
8. Bioorg. Med. Chem. Lett. 1998, 8, 687–690.
9. https://www.chem.purdue.edu/ghosh/research-hiv.htm (Accessed 12/11/2016)
10. Prezista (darunavir) FDA label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021976s021lbl.pdf (Accessed 12/11/2016)
11. Pediatric Postmarketing Pharmacovigilance and Drug Utilization Review for Prezista [NDA 202895 (oral suspension) and NDA 21976 (tablets)]. July 28, 2015.
12. J. Nat. Prod. 2016, 79, 629–661.