Pei Zhou

Overview:

Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidating the dynamic behavior of proteins during the process of recognition. Recent advances in NMR techniques have enabled the study of significantly larger proteins and protein complexes. These innovations have also led to faster and more accurate structure determination. My research interests focus on the exploration of molecular recognition and conformation variability of protein complexes in crucial biomedical processes using state-of-the-art NMR techniques.

Positions:

Professor of Biochemistry

Biochemistry
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1998

Harvard University

Post-Doct Fellow, Biological Chemistry

Harvard University

Grants:

Structural Biology and Biophysics Training Program

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Biochemical and functional investigation of the novel enzymatic activities of MESH1

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Regulation of Germline Stem Cell Division in Drosophila

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date

High sensitivity multi-purpose electron paramagnetic resonance spectroscopy for biotechnological and biomedical research

Administered By
Biochemistry
Awarded By
North Carolina Biotechnology Center
Role
Collaborating Investigator
Start Date
End Date

Discovery and validation of broadly effective LpxH inhibitors as novel therapeutics against multi-drug resistant Gram-negative pathogens

Administered By
Biochemistry
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer.

Cisplatin is a standard of care for lung cancer, yet platinum therapy rarely results in substantial tumor regression or a dramatic extension in patient survival. Here, we examined whether targeting Rev7 (also referred to as Mad2B, Mad2L2, and FANCV), a component of the translesion synthesis (TLS) machinery, could potentiate the action of cisplatin in non-small cell lung cancer (NSCLC) treatment. Rev7 loss led to an enhanced tumor cell sensitivity to cisplatin and dramatically improved chemotherapeutic response in a highly drug-resistant mouse model of NSCLC. While cisplatin monotherapy resulted in tumor cell apoptosis, Rev7 deletion promoted a cisplatin-induced senescence phenotype. Moreover, Rev7 deficiency promoted greater cisplatin sensitivity than that previously shown following targeting of other Pol ζ-proteins, suggesting that Pol ζ-dependent and -independent roles of Rev7 are relevant to cisplatin response. Thus, targeting Rev7 may represent a unique strategy for altering and enhancing chemotherapeutic response.
Authors
Vassel, F-M; Bian, K; Walker, GC; Hemann, MT
MLA Citation
Vassel, Faye-Marie, et al. “Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer.Proc Natl Acad Sci U S A, vol. 117, no. 46, Nov. 2020, pp. 28922–24. Pubmed, doi:10.1073/pnas.2016067117.
URI
https://scholars.duke.edu/individual/pub1464141
PMID
33144509
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
117
Published Date
Start Page
28922
End Page
28924
DOI
10.1073/pnas.2016067117

NCP activates chloroplast transcription by controlling phytochrome-dependent dual nuclear and plastidial switches

Authors
Yang, EJ; Yoo, CY; Liu, J; Wang, H; Cao, J; Li, F; Pryer, KM; Sun, T; Weigel, D; Zhou, P
MLA Citation
Yang, E. J., et al. “NCP activates chloroplast transcription by controlling phytochrome-dependent dual nuclear and plastidial switches.” Nature Communications, vol. 10, no. 1, Nature Publishing Group, 2019, pp. 1–13.
URI
https://scholars.duke.edu/individual/pub1465900
Source
manual
Published In
Nature Communications
Volume
10
Published Date
Start Page
1
End Page
13

Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.

Bacterial infections caused by multi-drug-resistant Gram-negative pathogens pose a serious threat to public health. Gram-negative bacteria are characterized by the enrichment of lipid A-anchored lipopolysaccharide (LPS) or lipooligosaccharide (LOS) in the outer leaflet of their outer membrane. Constitutive biosynthesis of lipid A via the Raetz pathway is essential for bacterial viability and fitness in the human host. The inhibition of early-stage lipid A enzymes such as LpxC not only suppresses the growth of Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter spp., and other clinically important Gram-negative pathogens but also sensitizes these bacteria to other antibiotics. The inhibition of late-stage lipid A enzymes such as LpxH is uniquely advantageous because it has an extra mechanism of bacterial killing through the accumulation of toxic lipid A intermediates, rendering LpxH inhibition additionally lethal to Acinetobacter baumannii. Because essential enzymes of the Raetz pathway have never been exploited by commercial antibiotics, they are excellent targets for the development of novel antibiotics against multi-drug-resistant Gram-negative infections.This Account describes the ongoing research on characterizing the structure and inhibition of LpxC and LpxH, the second and fourth enzymes of the Raetz pathway of lipid A biosynthesis, in the laboratories of Dr. Pei Zhou and Dr. Jiyong Hong at Duke University. Our studies have elucidated the molecular basis of LpxC inhibition by the first broad-spectrum inhibitor, CHIR-090, as well as the mechanism underlying its spectrum of activity. Such an analysis has provided a molecular explanation for the broad-spectrum antibiotic activity of diacetylene-based LpxC inhibitors. Through the structural and biochemical investigation of LpxC inhibition by diacetylene LpxC inhibitors and the first nanomolar LpxC inhibitor, L-161,240, we have elucidated the intrinsic conformational and dynamics difference in individual LpxC enzymes near the active site. A similar approach has been taken to investigate LpxH inhibition, leading to the establishment of the pharmacophore model of LpxH inhibitors and subsequent structural elucidation of LpxH in complex with its first reported small-molecule inhibitor based on a sulfonyl piperazine scaffold.Intriguingly, although our crystallographic analysis of LpxC- and LpxH-inhibitor complexes detected only a single inhibitor conformation in the crystal lattice, solution NMR studies revealed the existence of multiple ligand conformations that together delineate a cryptic ligand envelope expanding the ligand-binding footprint beyond that observed in the crystal structure. By harnessing the ligand dynamics information and structural insights, we demonstrate the feasibility to design potent LpxC and LpxH inhibitors by merging multiple ligand conformations. Such an approach has enabled us to rationally design compounds with significantly enhanced potency in enzymatic assays and outstanding antibiotic activities in vitro and in animal models of bacterial infection. We anticipate that continued efforts with structure and ligand dynamics-based lead optimization will ultimately lead to the discovery of LpxC- and LpxH-targeting clinical antibiotics against a broad range of Gram-negative pathogens.
Authors
MLA Citation
Zhou, Pei, and Jiyong Hong. “Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.Acc Chem Res, vol. 54, no. 7, Apr. 2021, pp. 1623–34. Pubmed, doi:10.1021/acs.accounts.0c00880.
URI
https://scholars.duke.edu/individual/pub1476489
PMID
33720682
Source
pubmed
Published In
Acc Chem Res
Volume
54
Published Date
Start Page
1623
End Page
1634
DOI
10.1021/acs.accounts.0c00880

REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.

REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.
Authors
Chatterjee, N; Whitman, MA; Harris, CA; Min, SM; Jonas, O; Lien, EC; Luengo, A; Vander Heiden, MG; Hong, J; Zhou, P; Hemann, MT; Walker, GC
MLA Citation
Chatterjee, Nimrat, et al. “REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.Proc Natl Acad Sci U S A, vol. 117, no. 46, Nov. 2020, pp. 28918–21. Pubmed, doi:10.1073/pnas.2016064117.
URI
https://scholars.duke.edu/individual/pub1464140
PMID
33168727
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
117
Published Date
Start Page
28918
End Page
28921
DOI
10.1073/pnas.2016064117

Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens.
Authors
Kwak, S-H; Cochrane, CS; Ennis, AF; Lim, WY; Webster, CG; Cho, J; Fenton, BA; Zhou, P; Hong, J
MLA Citation
Kwak, Seung-Hwa, et al. “Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.Bioorg Chem, vol. 102, Sept. 2020, p. 104055. Pubmed, doi:10.1016/j.bioorg.2020.104055.
URI
https://scholars.duke.edu/individual/pub1452342
PMID
32663666
Source
pubmed
Published In
Bioorg Chem
Volume
102
Published Date
Start Page
104055
DOI
10.1016/j.bioorg.2020.104055