Hongmin Li, PhD

Professor, Pharmacology and Toxicology
R. Ken and Donna Coit Endowed Chair in Drug Discovery

Hongmin Li, PhD, joined the College of Pharmacy, University of Arizona Tucson in 2020 from the Wadsworth Center, New York State Department of Health. During the last 20 years, my laboratory focuses on both basic and translational sciences. In basic science part, we investigate the structures, functions and mechanisms of essential macromolecules involved in various cellular actions and disease processes. The knowledge gained from these basic science studies leads to the second category, the drug discovery part where we develop novel biochemical and cellular assays for different drug targets, carry out high throughput screening (HTS) assays to identify novel target-based inhibitors, perform cellular antiviral/antifungal/anti-cancer assays, and conduct ADMET profiling and mouse model efficacy studies for lead compounds.

My laboratory has developed a research platform that integrates virology, mycology, bacteriology, RNA, biochemistry, structural biology, cellular biology, and in vivo animal model in the same lab. We also work closely with collaborators and colleagues in the aspects of medicinal chemistry, computational biology, immunology, cancer biology, and in vivo pharmacokinetics and pharmacodynamics (PK/PD).

The Li laboratory has been continuously funded by the NIH and various foundations since 2002. Currently, the main research focuses on development of therapeutics against cancers and human pathogens such as dengue virus, Zika virus, SARS-CoV-2, Cryptococcal fungi and Mycobacterium tuberculosis. Students and postdoctors joining in the lab will have opportunities to explore all areas in the Li laboratory, as stated above. We currently have multiple positions opening at all levels (undergraduate and graduate students, technician, and postdoc).  Please visit talent.arizona.edu to apply for open positions.

Research projects:

  1. Orthosteric and allosteric inhibition of flavivirus NS2B/NS3 protease complex. Viral protease is an attractive target for therapeutic intervention. The HIV and HCV proteases are good examples as antiviral targets. The flavivirus protease, a two-component complex consisting of viral proteins NS3 and NS2B (cofactor), is responsible for cleavage of the polyprotein precursor (PP) produced by the viral genome. Most attempts to develop flavivirus protease inhibitors have focused on the NS3 active site with very limited success. We have successfully developed high throughput screening (HTS) assays. Our pilot HTS was very successful, identifying several existing drugs as potent flavivirus protease inhibitors, with both in vitro and in vivo activities. The project is currently on-going to screen larger NIH libraries to identify novel inhibitors with new scaffolds. We are collaborating with medicinal chemists, experts in drug metabolism, computational biologists, and virologists to develop potent protease inhibitors with various mechanisms.
  2. Nanobodies as therapeutics for flavivirus management. All flaviviruses are coated with their own envelope (E) protein. Neutralizing antibodies against the E protein have been identified. However, due to antibody-dependent enhancement (ADE), these antibodies are not ideal candidates as therapeutics. In contrast, a single domain, termed VHH (variable domain of camelid heavy-chain-only antibody (HcAb)) or nanobody (Nb) has emerged as an effective drug candidate for various applications, including infectious disease management. Compared to conventional antibodies, Nbs do not have the Fc domain that is required for enhanced disease, thus eliminating ADE. In this project, we will screen Nb-containgin phage libraries, perform viral plaque reduction neutralization test, viral entry inhibition, ADE evaluation, viral resistance, affinity measurement, epitope mapping, co-crystal structure, Cryo-EM, and mutagenesis studies. We will generate both virus specific and broad-spectrum neutralizing Nbs for flavivirus management. We will follow up with in vivo pharmacokinetics and antiviral efficacy using animal disease models.
  3. Inteins as drug targets for intein-containing mycobacteria and fungi. Inteins are internal self-splicing protein elements that self-excise from their host proteins and catalyze ligation of the flanking sequences (exteins) with a natural peptide bond. Many human pathogens contain inteins in their genes. For example, Mycobacterium tuberculosis (Mtu) harbors inteins in three genes: RecA recombinase, DnaB helicase, and SufB iron-cluster assembly gene. All three functions are required for virulence, with DnaB and SufB being essential for bacterial growth. The fungi, Cryptococcus neoformans (Cne), C. gattii (Cga), and Aspergillus fumigatus (Afu), contain inteins in their Prp8 genes (Prp8: pre-mRNA processing 8, an essential component of spliceosome). It is worth noting that inteins only exist in certain microbes, mammals including human beings do not have intein elements in their genes. Based on these analyses, we hypothesize that inteins are attractive drug targets for management of intein-containing microbial infections. We have determined the crystal structures of the Prp8 intein, various forms of the RecA intein, and a class III DnaB intein. We showed that cisplatin, an FDA-approved chemotherapeutics, not only inhibits the intein splicing in vitro, but also significantly reduces the fungal burden in lungs using an in vivo cryptococcosis mouse model. Using genetic approaches, we have also generated an intein-free cryptococcal strain to characterize inhibitor specificity. Moreover, we have developed HTS assays to help screen intein splicing inhibitors. The project will proceed to HT screens.
  4. Mechanism, function and inhibition of the Hectd3 E3 ubiquitin ligase. Protein ubiquitination is sequentially mediated by three enzymes: the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) that controls substrate specificity. Recently we studied a HECT-containing E3 ligase, Hectd3, which has recently become a hot topic. Hectd3 is a much understudied E3 ligase with only a dozen publications to date. Hectd3 is considered an injurious gene that promotes cancer cell survival, enables pathogenesis of multiple sclerosis (MS), and facilitates infections of microbial pathogens such as intracellular bacteria Francisella novicida, Mycobacteria, and Listeria. Importantly, as a host factor, Hectd3 is dispensable for the host as Hectd3–/– mice were viable and normal. At mechanistic level, we and others found that Hectd3 interacts with and/or ubiquitinates multiple substrates (caspase-8, caspase-9, Malt1, TRAF3, HSP90, CRAF, and Stat3), leading to non-degradative polyubiquitination of target proteins, stabilizing them, and thus inducing drug resistance in cancer cells or promoting Th17 pathogenic T-cells differentiation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. For this project, we aim to investigate the mechanism, function, and inhibition of Hectd3. We will determine its complexes with substrate and the E2 conjugating enzyme using X-ray and Cryo-EM. We will also develop HTS assays to identify inhibitors. These basic and translational sciences will greatly advance our understanding of this novel E3 ligase and facilitate development of novel therapies for disease management.
Education & Post Graduate Training: 

BS, Physiology & Biophysics, Beijing University (China), 1990
MS, Molecular Biology, Institute of Biophysics, Chinese Academy of Sciences (China), 1993
PhD, Molecular Biology, Institute of Biophysics, Chinese Academy of Sciences (China), 1995
Postdoc, Molecular and Structural Immunology, Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institutes, Rockville MD, 2000

Select Publications

2020

Li Z, Xu J, Lang Y, et al. "JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both and ." ACS Infect Dis. 2020;6(10):2616-2628. PMCID: PMC7559020  PMID: 32866370
Li Z, Lang Y, Sakamuru S, et al. "Methylene blue is a potent and broad-spectrum inhibitor against Zika virus in vitro and in vivo." Emerging Microbes and Infections. 2020;9(1):2404-2016.
Woods D, Vangaveti S, Egbanum I, et al. "Conditional DnaB protein splicing is reversibly inhibited by zinc in mycobacteria." mBio. 2020;11(4):e01403-20.
Tharappel AMathew, Samrat SKumar, Li Z, Li H. "Targeting crucial host factors of SARS-CoV-2." ACS infect Dis. 2020.

2019

Fan X, Li H, Ding X, Zhang Q-Y. "Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, A Repurposed Drug with Poor Bioavailability." Drug Metabolism and Disposition. 2019;47(7):756-763.
Cho JJ, Xu Z, Parthasarathy U, et al. "Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation." Nat Commun. 2019;10(1):701. PMCID: PMC6370850  PMID: 30741923
Green CM, Li Z, Smith AD, et al. "Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing." PLoS Biol. 2019;17(10):e3000104. PMCID: PMC6805012  PMID: 31600193
Zhao J, Ciulla DA, Xie J, et al. "General Base Swap Preserves Activity and Expands Substrate Tolerance in Hedgehog Autoprocessing." J Am Chem Soc. 2019;141(46):18380-18384. PMCID: PMC7106946  PMID: 31682419

2018

Li Z, Sakamuru S, Huang R, et al. "Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease." Antiviral Res. 2018;150:217-225. PMCID: PMC5892443  PMID: 29288700
Kelley DS, Lennon CW, Li Z, et al. "Mycobacterial DnaB helicase intein as oxidative stress sensor." Nat Commun. 2018;9(1):4363. PMCID: PMC6195587  PMID: 30341292