Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine.
Hidaka, K., Kimura, T., Sankaranarayanan, R., Wang, J., McDaniel, K.F., Kempf, D.J., Kameoka, M., Adachi, M., Kuroki, R., Nguyen, J.T., Hayashi, Y., Kiso, Y.(2018) J Med Chem 61: 5138-5153
- PubMed: 29852069 
- DOI: https://doi.org/10.1021/acs.jmedchem.7b01709
- Primary Citation of Related Structures:  
5YOJ, 5YOK - PubMed Abstract: 
The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P 3 , P 2 , and P 2 ́ moieties. The derivatives with P 2 tetrahydrofuranylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.
Organizational Affiliation: 
Laboratory of Medicinal Chemistry, Faculty of Pharmaceutical Sciences , Kobe Gakuin University , Kobe 650-8586 , Japan.