Highly Potent HIV-1 Protease Inhibitors with Polycyclic-THF Ligands

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Track Code	2020-GHOS-68891
Categories	Chemistry and Chemical Analysis Pharmaceuticals
Keywords	Chemistry and Chemical Analysis Drug Development HIV/AIDS Medicinal Chemistry Pharmaceutical Analysis Pharmaceutical Research Pharmaceuticals Pharmacology
Public Abstract	NCS: Researchers at Purdue University have designed and developed a new class of highly potent HIV-1 protease inhibitors with polycyclic-THF ligands for treatment of human immunodeficiency virus type 1 (HIV-1). Improvement of current HIV protease inhibitors is needed to combat drug-resistant HIV strains. Although antiretroviral therapies (ART) have had a major impact on the AIDS epidemic, they have not eradicated HIV-1 in part due to the viral reservoirs remaining in blood and infected tissues. Purdue researchers developed novel protease inhibitors with improved properties over darunavir. In testing in vitro, the new inhibitors showed 100-fold increased antiviral activity against drug resistant strains of HIV-1 relative to darunavir. The high yielding synthetic schemes (79-90%) of these inhibitors and derivatives offer an encouraging potential for reaction scale-up. Moreover, structurally, these compounds are expected to have good pharmacokinetic properties for drug development. Technology Validation: High resolution crystal structures of inhibitor bound wild-type HIV-1 protease have shown increased binding properties compared to darunavir. The new protease inhibitors have also been tested in vitro wherein they exhibit improved treatment of HIV-1 over darunavir by 100-fold. Advantages: - High antiviral activity against resistant HIV-1 - Structurally promising pharmacokinetic properties - High yield synthesis Applications: - HIV-1 therapeutics - Drug discovery Related Publications: "Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand to Combat Multidrug-Resistant HIV Variants" Journal of Medicinal Chemistry DOI: 10.1021/acs.jmed.chem.7b00172 "Design of Highly Potent, Dual Acting and Central Nervous System Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants" ChemMedChem DOI: 10.1002/cmdc.201700824
People	Ghosh, Arun K (Project leader) Kovela, Satish Mitsuya, Hiroaki
Intellectual Property	Application Date Sep 16, 2022 Type NATL-Patent Country of Filing United States Patent Number (None) Issue Date (None) Application Date Jan 18, 2021 Type PCT-Gov. Funding Country of Filing WO Patent Number (None) Issue Date (None) Application Date Jan 18, 2021 Type NATL-Patent Country of Filing Canada Patent Number (None) Issue Date (None) Application Date Jan 18, 2021 Type NATL-Patent Country of Filing Europe Patent Number (None) Issue Date (None) Application Date Jan 18, 2021 Type NATL-Patent Country of Filing Japan Patent Number (None) Issue Date (None) Application Date Mar 18, 2020 Type Provisional-Gov. Funding Country of Filing United States Patent Number (None) Issue Date (None)
Contact OTC	Purdue Office of Technology Commercialization The Convergence Center 101 Foundry Drive, Suite 2500 West Lafayette, IN 47906 Phone: (765) 588-3475 Fax: (765) 463-3486 Email: otcip@prf.org