Xue Zhi Zhao, Ph.D.
Dr. Zhao has been a pioneer in the field of anti-AIDS agents, with a particular focus on developing inhibitors of HIV-1 integrase (IN). His recent studies have concentrated on the discovery of inhibitors that retain efficacy against virus harboring mutant forms of IN integrase, which are resistant to current FDA-approved drugs. These efforts are being done in collaboration with the NCI laboratories of Drs. Yves Pommier (Developmental Therapeutics Branch) and Stephen Hughes (HIV Drug Resistance Program). His compounds offer potential leads for further structural variation that may ultimately yield clinical agents capable of overcoming problems associated with the development of resistance.
1) chemical biology, 2) medicinal chemistry, 3) organic chemistry, 4) drug design, 5) HIV, 6) integrase
The main focus of my research is to develop HIV-1 integrase (IN) as potential AIDS therapeutics. Raltegravir (RAL) (Merck, October 2007), Elvitegravir (EVG) (Gilead, August 2012) and Dolutegravir (DTG) (GSK, August 2013) are currently the only IN strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However the ability of mutant forms of IN to exhibit drug resistance emphasizes the need to develop additional agents that retain efficacy against resistant mutants. My work is being done in collaboration with the NCI laboratories of Dr. Yves Pommier and Stephen Hughes. Through an extensive synthetic effort, I examined 2,3-dihdroxybenzoylhydrazides and amides as new classes of diketoacid (DKA) mimetics. These agents utilized methylene and oxomethylene bridges to form bicyclic variants of these 2,3-dihdroxybenzoylhydrazides and amides in which key metal-chelating heteroatoms are conformationally constrained to coplanarity. This work resulted in the discovery of structurally simple 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones that exhibit potent integrase inhibition at low nanomolar concentrations and display good antiviral potencies in HIV-1-infected cells. Based on these integarse inhibitors, I further developed 6,7-dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors. Co-crystal structures of these inhibitors in complex with the Prototype Foamy Virus (PFV) intasome disclosed their binding mode. I also examined tricyclic and bicyclic hydroxy-1H-pyrrolopyridine-trione containing INSTIs in an effort to overcome cytotoxicity of our earlier series of catechol-containing inhibitors. Most recently, I have developed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors. Members of this series show single-digit nanomolar antiviral potencies against cells transfected with wild-type (WT) IN, while having improved antiviral efficacies against a panel of cells transfected with viral constructs carrying the major forms of resistant mutant IN. Low cytotoxicity in many cases results in selectivity indices (CC50/EC50) of greater than 50,000. These compounds offer potential leads for further structural variation that may ultimately yield clinical agents capable of overcoming problems associated with the development of resistance.
Selected Key Publications
- J. Med. Chem. 60(17): 7315-7332, 2017. [ Journal Article ]
HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases.ACS Chem. Bio. 11(4): 1074-81, 2016. [ Journal Article ]
6,7-Dihydroxyisoindolin-1-one and 7,8-Dihydroxy-3,4-Dihydroisoquinolin- 1(2H)-one Based HIV-1 Integrase Inhibitors.Curr. Top. Med. Chem. 16(4): 435-40, 2016. [ Journal Article ]
Application of Oxime-diversification to Optimize Ligand Interactions within a Cryptic Pocket of the Polo-like Kinase 1 Polo-box Domain.Bioorg. Med. Chem. Lett. 26(20): 5009-5012, 2016. [ Journal Article ]
4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing Compounds Having High Potency against Raltegravir-resistant Integrase Mutants of HIV-1.J. Med. Chem. 57(12): 5190-202, 2014. [ Journal Article ]
Dr. Zhao received his Ph.D. degree in organic chemistry from Lanzhou University with professor Yongqiang Tu in 2005. He then joined the Laboratory of Medicinal Chemistry, NCI as a NIH Visiting Fellow under the direction of Dr. Terrence Burke. He was appointed as a Research Fellow in 2008 and subsequently in 2010 as a Staff Scientist in the Chemical Biology Laboratory. In 2019, he was promoted as a CCR Associate Scientist. His research focuses on developing HIV-1 integrase inhibitors as potential anti-AIDS agents and tyrosyl-DNA phosphodiesterase 1 inhibitors as anti-cancer agents. He has also developed a series of peptide polo-like kinase polo-box domain-binding inhibitors as anti-cancer agents.