Wuyuan Lu

B.S. Nanjing University, China 1984; Ph.D. Purdue University, West Lafayette 1994; Post-Doctoral The Scripps Research Institute, La Jolla 1996

• Protein engineering via total chemical protein synthesis. As chemical engineers of proteins, we are interested in knowing what happens to functional properties of proteins when their side chains and backbone structures are altered in a way that is genetically unattainable. To accomplish this unconventional task, we functionally and structurally characterize proteins that are chemically assembled from (coded and non-coded) individual amino acids. This “chemical protein engineering” approach allows us to address, from a different perspective, important unsolved problems in protein science, thus broadening our knowledge and deepening our understanding of how proteins function at the molecular level.
• Defensins – structure, function and mechanisms of action. Defensins are a family of 2-5 kDa, disulfide-bridged cationic antimicrobial peptides expressed in leukocytes and epithelial cells. They are broadly active against bacteria, fungi, and viruses, playing important roles in innate host defense against microbial infection. Some defensins also neutralize secreted bacterial toxins and can bind host cell receptors to trigger innate inflammatory and adaptive immune responses. Our studies are aimed at deciphering the molecular determinants of diverse functions of human defensins and elucidating their mechanisms of action in a variety of biological processes. Such knowledge may help design new anti-infective peptides to fight off infectious diseases.• Antiviral and antitumor peptides for targeted molecular therapy. Peptide inhibition of protein-protein interactions is a promising route for the development of novel classes of therapeutic agents for targeted molecular therapy. Compared with small molecule inhibitors, peptides are capable of antagonizing target proteins with high affinity and unsurpassed specificity. This line of research centers on applying the contemporary tools of synthetic protein chemistry, phage display, structural biology, and drug delivery to the discovery of peptide antagonists with desirable pharmacokinetic properties and functionalities that may be explored for therapeutic use. Our targets include but not limited to HIV-1 matrix and capsid proteins as well as oncogenic proteins that negatively regulate the tumor suppressor protein p53.

Selected Publications

1. Liu M, Li C, Pazgier M, Li C, Mao Y, Lv Y, Gu B, Wei G, Zhan C, Yuan W, Lu W-Y, Lu W (2010). D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms.Proc Natl Acad Sci USA 107(32):14321-6. (Featured by SciBXhttp://www.nature.com/scibx/journal/v3/n31/full/scibx.2010.952.html)
2. Li C, Li X, Lu W (2010). Total chemical synthesis of human T-cell leukemia virus type 1 protease via native chemical ligation. Biopolymers 94(4):487-494.
3. Smith JG, Silvestry M, Lindert S, Lu W, Nemerow GR, Stewart PL (2010). Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization. PLoS Pathogens 6(6):e1000959
4. Moulaei T, Stuchlik O, Reed M, Yuan W, Pohl J, Lu W, Haugh-Krumpe L, O’Keefe BR, Wlodawer A (2010). Topology of the disulfide bonds in the antiviral lectin scytovirin. Protein Sci 19(9):1649-61.
5. Liu M, Pazgier M, Li C, Yuan W, Li C, Lu W (2010). A left-handed solution to peptide inhibition of the p53-MDM2 interaction. Angew Chem Int Ed Engl 49(21):3649-52.
6. Li S, Bozzo L, Wu Z, Lu W, Romerio F (2010). The HIV-1 matrix protein p17 activates the transcription factors c-Myc and CREB in human B cells. New Microbiol 33(1):13-24.
7. Li C, Pazgier M, Li J, Li C, Liu M, Zou G, Li Z, Chen J, Tarasov SG, Lu W-Y, Lu W (2010). Limitations of peptide retro-inverso isomerization in molecular mimicry. J Biol Chem 285(25):19572-81.
8. Li C, Pazgier M, Li C, Yuan W, Liu M, Wei G, Lu WY, Lu W (2010). Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions. J Mol Biol 398(2):200-13.
9. Wei G, Pazgier M, de Leeuw E, Rajabi M, Li J, Zou G, Jung G, Yuan W, Lu WY, Lehrer RI, Lu W (2010). Trp-26 imparts functional versatility to human alpha-defensin HNP1. J Biol Chem 285(21):16275 85. (Selected by Faculty of 1000 Biology as a Recommended Paperhttp://www.f1000biology.com/article/id/4641956/evaluation)
10. de Leeuw E, Li C, Zeng P, Li C, Buin MD, Lu WY, Breukink E, Lu W (2010). Functional interaction of human neutrophil peptide 1 with the cell wall precursor lipid II. FEBS Lett 584(8):1543-8.
11. Zhang Y, Doherty T, Li J, Lu W, Barinka C, Lubkowski J, Hong M (2010). Resonance assignment and three-dimensional structure determination of a human alpha-defensin, HNP-1, by solid-state NMR. J Mol Biol 397(2):408-422.
12. Lafferty MK, Sun L, DeMasi L, Lu W, Garzino-Demo A (2010). CCR6 ligands inhibit HIV by inducing APOBEC3G. Blood 115(8):1564-71.
13. Li C, Pazgier M, Liu M, Lu WY, Lu W (2009). Apamin as a template for structure-based rational design of potent peptide activators of p53. Angew Chem Int Ed Engl 48(46):8712-5.
    (Featured by SciBX http://www.nature.com/scibx/journal/v2/n41/full/scibx.2009.1529.html)
14. Wei G, de Leeuw E, Pazgier M, Yuan W, Zou G, Wang J, Ericksen B, Lu WY, Lehrer RI, Lu W (2009). Through the looking glass, mechanistic insights from enantiomeric human defensins. J Biol Chem284(42):29180-92.
15. Miles K, Clarke DJ, Lu W, Sibinska Z, Beaumont PE, Davidson DJ, Barr TA, Campopiano DJ, Gray M (2009). Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins.J Immunol 183(3):2122-32.
16. de Leeuw E, Rajabi M, Zou G, Pazgier M, Lu W (2009). Selective arginines are important for the antibacterial activity and host cell interaction of human alpha-defensin 5. FEBS Lett 583(15):2507-12.
17. Lehrer RI, Jung G, Ruchala P, Wang W, Micewicz ED, Waring AJ, Gillespie EJ, Bradley KA, Ratner AJ, Rest RF, Lu W (2009). Human alpha-defensins inhibit hemolysis mediated by cholesterol-dependent cytolysins. Infect Immun 77(9):4028-40.
18. Lehrer RI, Jung G, Ruchala P, Andre S, Gabius HJ, Lu W (2009). Multivalent binding of carbohydrates by the human alpha-defensin, HD5. J Immunol 183(1):480-90.
19. Pazgier M, Liu M, Zou G, Yuan W, Li C, Li C, Li J, Monbo J, Zella D, Tarasov SG, Lu W (2009). Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci USA106(12):4665-70.
20. Gryllos I, Tran-Winkler HJ, Cheng MF, Chung H, Bolcome R 3rd, Lu W, Lehrer RI, Wessels MR (2008). Induction of group A Streptococcus virulence by a human antimicrobial peptide. Proc Natl Acad Sci USA105(43):16755-60.
21. Wang S, Han J, Wang Y, Lu W, Chi C (2008). Design of peptide inhibitors for furin based on the C-terminal fragment of histone H1.2. Acta Biochim Biophys Sin 40(10):848-54.
22. Li C, Liu M, Monbo J, Zou G, Li C, Yuan W, Zella D, Lu WY, Lu W (2008). Turning a scorpion toxin into an antitumor miniprotein. J Am Chem Soc 130(41):13546-8.
    (Selected by Faculty of 1000 Biology as a Must Read Paper and highlighted by ChemBioChem
    http://www.f1000biology.com/article/id/1122948/evaluation
    http://www3.interscience.wiley.com/journal/122240983/abstract)
23. Zou G, de Leeuw E, Lubkowski J, Lu W (2008). Molecular determinants for the interaction of human neutrophil alpha defensin 1 with its propeptide. J Mol Biol 381(5):1281-91.
24. Li C, Wu Z, Liu M, Pazgier M, Lu W (2008). Chemically synthesized human survivin does not inhibit caspase-3. Protein Sci 17(9):1624-9.
25. Rajabi M, de Leeuw E, Pazgier M, Li J, Lubkowski J, Lu W (2008). The conserved salt bridge in human alpha-defensin 5 is required for its precursor processing and proteolytic stability. J Biol Chem283(31):21509-18.
    (Selected as a Paper of the Week by the JBC Editorial Board http://www.jbc.org/content/283/31/e99941.full)
26. Klotman ME, Rapista A, Teleshova N, Micsenyi A, Jarvis GA, Lu W, Porter E, Chang TL (2008). Neisseria gonorrhoeae-induced human defensins 5 and 6 increase HIV infectivity: role in enhanced transmission. J Immunol 180(9):6176-85.