About

Hengming Ke is a Professor of Biochemistry and Biophysics at the University of North Carolina at Chapel Hill. His research focuses on the structure and function of medically important proteins, utilizing X-ray protein crystallography and biochemistry techniques. His work includes the enzymatic and structural characterization of cyclic nucleotide phosphodiesterases (PDEs), structure-based design of PDE selective inhibitors, and the discovery of novel metallo-β-lactamase (MBL) inhibitors to combat antibiotic-resistant bacteria. Ke's group has solved over 30 crystal structures of various PDE families and has recently identified highly selective inhibitors for PDE4, PDE5, and PDE9. Additionally, his research involves designing inhibitors against NDM-1, a metallo-β-lactamase enzyme responsible for antibiotic resistance in superbugs, aiming to develop therapeutic agents to address multidrug resistance.

Research topics

• Pharmacology
• Biochemistry
• Chemistry
• Internal medicine
• Stereochemistry
• Medicine

Selected publications

• Design, Synthesis, and Evaluation of Selective PDE4 Inhibitors for the Therapy of Pulmonary Injury

  Journal of Medicinal Chemistry · 2025-01-23 · 9 citations

  article

  Pulmonary inflammation is the main cause of lung injury. Phosphodiesterase 4 (PDE4) is a promising anti-inflammatory target for the treatment of respiratory diseases. Herein, we designed and synthesized 43 compounds in two novel series of benzimidazole derivatives as PDE4 inhibitors. Among them, compound A5 showed highly selective inhibition of PDE4, good safety, and liver microsomal stability in vitro. A5 administration remarkably attenuated inflammatory infiltration and pathologic injury of the lung in models of acute lung injury in mice and chronic obstructive pulmonary disease (COPD) in mice. In addition, A5 enhanced sputum secretion, relieved cough in mice, and inhibited phosphorylation of p38 MAP kinase, an important protein in the regulation of lung injury. Overall, A5, as an effective PDE4 inhibitor without acute toxicity and gastrointestinal reaction, may be a potent candidate for the treatment of pulmonary injury.

  PublisherDOI

• M2 type Macrophages promote OSCC progress via conferring resistance to Erastin-induced ferroptosis

  Scientific Reports · 2025-08-05

  preprintOpen access

  INTRODUCTION: M2 type macrophages could promote oral squamous cell carcinoma (OSCC) progress. Ferroptosis is a newly discovered type of programmed cell death and inhibition of ferroptosis in many tumor models could promote tumor progression. This study aims to investigate whether M2 type macrophages could influence the progression of OSCC by regulating the ferroptosis of tumor cells. METHODS: Immunohistochemical staining was performed to verify the correlation between the expression of CD206 representing M2 type macrophage infiltration in tumor tissue, and GPX4 representing the ability to resist ferroptosis in vivo. In vitro, treat OSCC cells with ferroptosis inducers at different concentrations, detect their effects on ferroptosis, and meanwhile observe their impacts on the proliferation, migration and invasion abilities of OSCC cells; stimulate macrophages to generate different polarization states and identify them. Then, OSCC cells with different levels of ferroptosis were treated with products from macrophages of different polarized states, and the effects on ferroptosis and proliferation, migration and invasion ability of OSCC cells were observed and detected. RESULTS: CD206 and GPX4 expression in OSCC clinical samples were positively correlated. With the downregulation of ferroptosis, the proliferation, migration and invasion of OSCC cells were inhibited, and M2 type macrophages can upregulate ferroptosis of OSCC cells, meanwhile enhancing their proliferation, migration and invasion capacity. CONCLUSIONS: Our studies demonstrated M2 type macrophages could accelerate the progression of OSCC by augmenting the capacity of OSCC cells to resist ferroptosis. CLINICAL SIGNIFICANCE: Our studies might offer insights for the application of ferroptosis or macrophage polarization in the therapy of OSCC.

  PublisherOA PDFDOI

• Cyclic nucleotide phosphodiesterases as drug targets

  Pharmacological Reviews · 2025-01-22 · 22 citations

  reviewOpen access

  Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.

  PublisherDOI

• Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

  European Journal of Medicinal Chemistry · 2024-10-09 · 8 citations

  articleSenior authorCorresponding
  PublisherDOI

• Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases

  Medicinal Research Reviews · 2024-01-27 · 18 citations

  reviewSenior authorCorresponding

  Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3',5'-monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease-modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs.

  PublisherDOI

• Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis

  Journal of Medicinal Chemistry · 2024-11-13 · 5 citations

  articleCorresponding

  Psoriasis is a complex and chronic inflammatory disease. Current drugs help control the symptoms of psoriasis but make no cure, urging discovery of novel drugs. We report in this paper the discovery of new phosphodiesterase 4 (PDE4) inhibitors for treatment of psoriasis. We designed and synthesized 45 new compounds, among which 14h exhibited IC50 of 0.57 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 14h inhibited release of inflammatory cytokines of TNF-α (IC50 = 34.2 μM) and IL-6 (IC50 = 40.9 μM) in Raw264.7 cells and reduced the expression of IL-1β and IL-17A in the skin of psoriasis mice. In addition, 14h alleviated IMQ-induced psoriasis in the mouse model and reduced the erythema level, scales, and thickness of the back skin of the mice. In short, our results suggested that PDE4 inhibitor 14h is a strong candidate for the topical treatment of psoriasis.

  PublisherDOI

• Microbiota for production of wine with enhanced functional components

  Food Science and Human Wellness · 2023-03-21 · 26 citations

  articleOpen access

  Microbial communities during winemaking are diverse and change throughout the fermentation process. Microorganisms not only drive alcohol fermentation, flavor and aroma, but also enhance wine functional components such as extraction of polyphenols from the berries, production of γ-aminobutyric acid, hydroxytyrosol and melatonin. Polyphenols such as resveratrol, catechin and quercetin determine the functional quality of the wine. Moderate wine consumption, particularly red wine has been associated with functional benefits to human health, which includes anti-inflammation, promoting healthy aging, prevention of cardiovascular diseases, cancers, type 2 diabetes and metabolic syndrome. Indeed, the management of microbiota allows the production of wine with distinct features and functional components that benefits human health. This review scrutinizes the possible contributions of wine microbiota to the production of wine with enhanced functional components and highlights the contributions of Saccharomyces and non-Saccharomyces yeasts and bacteria to enhance wine functional components during winemaking. Thus, contributing to the dissemination of the benefits of light to moderate wine intake to human health.

  PublisherDOI

• Cyclophilin A complexed with a fragment of HIV-1 gag protein: insights into HIV-1 infectious activity

  UNC Libraries · 2021-10-29 · 4 citations

  articleOpen access

  BACKGROUND: Cyclophilin A (CyPA), a receptor of the immunosuppressive drug cyclosporin A, catalyzes the cis-trans isomerization of peptidyl-prolyl bonds and is required for the infectious activity of human immunodeficiency virus type 1 (HIV-1). The crystal structure of CyPA complexed with a fragment of the HIV-1 gag protein should provide insights into the nature of CyPA-gag interactions and may suggest a role for CyPA in HIV-1 infectious activity. RESULTS: The crystal structure of CyPA complexed with a 25 amino acid peptide of HIV-1 gag capsid protein (25-mer) was determined and refined to an R factor of 0.195 at 1.8 A resolution. The sequence Ala88-Gly89-Pro90-Ile91 of the gag fragment is the major portion to bind to the active site of CyPA. Two residues of the 25-mer (Pro90-Ile91) bind to CyPA in a similar manner to two residues (Pro-Phe) of the CyPA substrate, succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (AAPF). However, the N-terminus of the 25-mer (Ala88-Gly89) exhibits a different hydrogen-bonding pattern and molecular conformation than AAPF. The peptidyl-prolyl bond between Gly89 and Pro90 of the 25-mer has a trans conformation, in contrast to the cis conformation observed in other known CyPA-peptide complexes. The residue preceding proline, Gly89, has an unfavorable backbone conformation usually only adopted by glycine. CONCLUSIONS: The unfavorable backbone conformation of Gly89 of the gag 25-mer fragment suggests that binding between HIV-1 gag protein and CyPA requires a special sequence, Gly-Pro. Thus, in HIV-1 infectivity, CyPA is likely to function as a chaperone, rather than as a cis-trans isomerase. However, the observation of similarities between the C termini of the 25-mer and the substrate AAPF means that the involvement of the cis-trans isomerase activity of CyPA cannot be completely ruled out.

  PublisherDOI

• Three-Dimensional Structures of PDE4D in Complex with Roliprams and Implication on Inhibitor Selectivity

  UNC Libraries · 2021-06-24

  articleOpen access

  AbstractSelective inhibitors against the 11 families of cyclic nucleotide phosphodiesterases (PDEs) are used to treat various human diseases. How the inhibitors selectively bind the conserved PDE catalytic domains is unknown. The crystal structures of the PDE4D2 catalytic domain in complex with (R)- or (R,S)-rolipram suggest that inhibitor selectivity is determined by the chemical nature of amino acids and subtle conformational changes of the binding pockets. The conformational states of Gln369 in PDE4D2 may play a key role in inhibitor recognition. The corresponding Y329S mutation in PDE7 may lead to loss of the hydrogen bonds between rolipram and Gln369 and is thus a possible reason explaining PDE7's insensitivity to rolipram inhibition. Docking of the PDE5 inhibitor sildenafil into the PDE4 catalytic pocket further helps understand inhibitor selectivity.

  PublisherDOI

• The Role of Probiotics in Purine Metabolism, Hyperuricemia and Gout: Mechanisms and Interventions

  Food Reviews International · 2021-04-14 · 55 citations

  article

  Hyperuricemia and gout are metabolic diseases characterized with high serum urate and impact human health significantly. Although some drugs have been developed to treat gout, hyperuricemia represents a substantial health problem. Reducing purine absorption through intestinal microbiota, which can be managed through intake of probiotics, emerges as a promising way to reverse elevated serum urate. Probiotics have shown several benefits such as immune modulation and improvement of intestinal functions. Therefore, this review briefly summarizes purine metabolism and molecular mechanisms for hyperuricemia and gout with the focus on recent development on the use of probiotics to alleviate hyperuricemia and gout.

  PublisherDOI

Recent grants

• NIH Grant R01AI033072

  NIH · $871k · 1998

• NIH Grant R01GM059791

  NIH · $3.0M · 2016

Frequent coauthors

• Huanchen Wang

  National Institute of Environmental Health Sciences

  122 shared

• Qing Huai

  61 shared

• Howard Robinson

  New York University Press

  41 shared

• Yudong Liu

  Xiangya Hospital Central South University

  33 shared

• Manna Huang

  Sun Yat-sen University

  32 shared

• Yongxian Shao

  Guangzhou Medical University

  30 shared

• Hai‐Bin Luo

  Hainan University

  30 shared

• Wenjun Cui

  Wuhan University of Technology

  27 shared

Labs

• UNC Department of Biochemistry and BiophysicsPI