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Scientific Overview Research Interest Summary Principal Investigators    Yuri Bushkin, Ph.D.
   Theresa Chang, Ph.D.
   Neeraj Chauhan, Ph.D.
   Véronique Dartois, Ph.D.
   Karl Drlica, Ph.D.
   David Dubnau, Ph.D.
   Eliseo A. Eugenin, Ph.D.
   Marila Gennaro, M.D.
   Gilla Kaplan, Ph.D.
   Fred Kramer, Ph.D.
   Barry Kreiswirth, Ph.D.
   Min Lu, Ph.D.
   Leonard Mindich, Ph.D.
   Arkady Mustaev, Ph.D.
   Jyothi Nagajyothi, Ph.D.
   David Perlin, Ph.D.
   Richard Pine, Ph.D.
   Abraham Pinter, Ph.D.
   Marcela Rodriguez, Ph.D.
   Selvakumar Subbian, Ph.D.
   Sanjay Tyagi, Ph.D.
   Christopher Vinnard, M.D.
   Chaoyang Xue, Ph.D.
   Xilin Zhao, Ph.D.

   Research Faculty
   Liang Chen, Ph.D.
   Eugenie Dubnau, Ph.D.
   Jeanette Hahn, Ph.D.
   Salvatore Marras, Ph.D.
   Lanbo Shi, Ph.D.
   Yanan Zhao, Ph.D.

Emeritus Faculty Recent Publications
 
Min Lu, Ph.D.

Research Summary  |  Selected Publications   |  C.V.
 

Public Health Research Institute Center and
at the International Center for Public Health
New Jersey Medical School - Rutgers, The State University of New Jersey
225 Warren Street
Newark, New Jersey 07103, USA

Phone: (973) 854-3360
e-mail: lum1@njms.rutgers.edu



Research Summary

Despite heroic efforts, the development of a safe and effective preventative HIV-1 vaccine remains elusive. And there is no pharmacologic strategy in sight that can eradicate persistent HIV-1 to bring the goal of an AIDS-free generation within our reach. Dr. Lu’s research seeks to address both of these fundamental problems. His approach is to define the detailed molecular mechanisms that underlie HIV-1 entry into target cells, specifically how HIV-1 uses its envelope glycoprotein (Env) to fuse with the target cell membrane, and how to inhibit this process with specific drug candidates and virus-neutralizing antibodies.

HIV-1 Env is thought to locate on the surface of the virion as a labile trimeric complex comprising three gp120 outer subunits non-covalently associated with three gp41 inner subunits that are anchored to the viral envelope. Upon engagement with its receptor CD4 and a co-receptor (CCR5 or CXCR4), the prefusion Env complex undergoes a regulated sequence of conformational changes in gp41, driven by formation of an energetically stable trimer of alpha-helical hairpins, which couples protein refolding directly to virus-cell membrane fusion, enabling viral entry. Dr. Lu’s laboratory aims to elucidate the molecular basis of each fusogenic structural transition, thereby guiding rational, structure-based efforts to design new immunogens and fusion inhibitors.

The design of immunogens able to elicit broadly reactive neutralizing antibodies is the holy grail of HIV-1 research. The general lack of a neutralizing antibody response would seem to reflect a conformational shielding of conserved functional epitopes within the prefusion Env complex. Dr. Lu’s laboratory determined the crystal structures of two newly identified coiled-coil domains in gp41 that are metastable and may thus correspond to prefusion form of the protein. The Lu lab currently uses protein engineering to create stable recombinant soluble Env proteins for structural studies, and to correlate specific gp41-gp41 interactions with the corresponding structural, functional and immunogenic properties of Env. A long-term goal is to develop stable immunogens capable of displaying the authentic prefusion Env trimer that is sufficiently long-lived to elicit antibodies that bind the cognate epitopes on infectious viruses.

The fusion-inhibiting drug enfuvirtide is used for salvage therapy in patients with multidrug-resistant HIV-1. However, its clinical use is limited by the requirement for parenteral delivery and the high cost of therapy. Despite intensive efforts over many years by researchers in academic and industrial laboratories, the search for orally bioavailable small-molecule HIV-1 fusion inhibitors targeting gp41 has been frustrating. Dr. Lu’s laboratory has used structural and chemical biology approaches to identify a novel small-molecule fusion inhibitor that acts to stabilize the prefusion Env complex against receptor-induced activation. Importantly, atomic-level structural information enables deriving principles that govern binding of small molecules to gp41. This knowledge in turn has provided a basis for successful lead optimization. In collaborative efforts, Dr. Lu and his colleagues are seeking to develop a potent small-molecule gp41 fusion inhibitor for the treatment and prevention of HIV-1 infection.




Selected Publications

Teplova M, Malinina L, Darnell JC, Song J, Lu M, Abagyan R, Musunuru K, Teplov A, Burley SK, Darnell RB, Patel DJ (2011) Protein-RNA and protein-protein recognition by dual KH1/2 domains of the neuronal splicing factor Nova-1. Structure 19: 930-944. PMI: 21742260

Denton PW, Othieno F, Martinez-Torres F, Zou W, Krisko JF, Fleming E, Zein S, Powell DA, Wahl A, Kwak YT, Welch BD, Kay MS, Payne DA, Gallay P, Appella E, Estes JD, Lu M, Garcia JV (2011) One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol 85: 7582-7593. PMI: 21593172

York J, Berry JD, Stroher U, Li Q, Feldmann H, Lu M, Trahey M, Nunberg JH (2010) An antibody directed against the fusion peptide of Junin virus envelope glycoprotein GPC inhibits pH-induced membrane fusion. J Virol 84: 6119-6129. PMI: 20392854

Porotto M, Rockx B, Yokoyama CC, Talekar A, Devito I, Palermo LM, Liu J, Cortese R, Lu M, Feldmann H, Pessi A, Moscona A (2010) Inhibition of Nipah virus infection in vivo: targeting an early stage of paramyxovirus fusion activation during viral entry. PLoS Pathog 6: e1001168. PMI: 21060819

Liu J, Deng Y, Li Q, Dey AK, Moore JP, Lu M (2010) Role of a putative gp41 dimerization domain in human immunodeficiency virus type 1 membrane fusion. J Virol 84: 201-209. PMI: 19846514

Banerjee K, Klasse PJ, Sanders RW, Pereyra F, Michael E, Lu M, Walker BD, Moore JP (2010) IgG subclass profiles in infected HIV type 1 controllers and chronic progressors and in uninfected recipients of Env vaccines. AIDS Res Hum Retroviruses 26: 445-458. PMI: 20377426

Liu J, Deng Y, Dey AK, Moore JP, Lu M (2009) Structure of the HIV-1 gp41 membrane-proximal ectodomain region in a putative prefusion conformation. Biochemistry 48: 2915-2923. PMI: 19226163

Horne WS, Johnson LM, Ketas TJ, Klasse PJ, Lu M, Moore JP, Gellman SH (2009) Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers. Proc Natl Acad Sci U S A 106: 14751-14756. PMI: 19706443

Gunasekar SK, Asnani M, Limbad C, Haghpanah JS, Hom W, Barra H, Nanda S, Lu M, Montclare JK (2009) N-terminal aliphatic residues dictate the structure, stability, assembly, and small molecule binding of the coiled-coil region of cartilage oligomeric matrix protein. Biochemistry 48: 8559-8567. PMI: 19681593

Eggink D, Langedijk JP, Bonvin AM, Deng Y, Lu M, Berkhout B, Sanders RW (2009) Detailed mechanistic insights into HIV-1 sensitivity to three generations of fusion inhibitors. J Biol Chem 284: 26941-26950. PMI: 19617355

Dey AK, David KB, Lu M, Moore JP (2009) Biochemical and biophysical comparison of cleaved and uncleaved soluble, trimeric HIV-1 envelope glycoproteins. Virology 385: 275-281. PMI: 19135223

Berro R, Sanders RW, Lu M, Klasse PJ, Moore JP (2009) Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry. PLoS Pathog 5: e1000548. PMI: 19680536

Wang D, Lu M, Arora PS (2008) Inhibition of HIV-1 fusion by hydrogen-bond-surrogate-based alpha helices. Angew Chem Int Ed Engl 47: 1879-1882. PMI: 18224636

Liu J, Wang D, Zheng Q, Lu M, Arora PS (2008) Atomic structure of a short alpha-helix stabilized by a main chain hydrogen-bond surrogate. J Am Chem Soc 130: 4334-4337. PMI: 18331030

Eggink D, Baldwin CE, Deng Y, Langedijk JP, Lu M, Sanders RW, Berkhout B (2008) Selection of T1249-resistant human immunodeficiency virus type 1 variants. J Virol 82: 6678-6688. PMI: 18434391

Eggink D, Baldwin CE, Deng Y, Langedijk JP, Lu M, Sanders RW, Berkhout B (2008) Selection of T1249-resistant human immunodeficiency virus type 1 variants. J Virol 82: 6678-6688. PMI: 18434391

Deng Y, Liu J, Zheng Q, Li Q, Kallenbach NR, Lu M (2008) A heterospecific leucine zipper tetramer. Chem Biol 15: 908-919. PMI: 18804028

Porotto M, Carta P, Deng Y, Kellogg GE, Whitt M, Lu M, Mungall BA, Moscona A (2007) Molecular determinants of antiviral potency of paramyxovirus entry inhibitors. J Virol 81: 10567-10574. PMI: 17652384

Porotto M, Carta P, Deng Y, Kellogg GE, Whitt M, Lu M, Mungall BA, Moscona A (2007) Molecular determinants of antiviral potency of paramyxovirus entry inhibitors. J Virol 81: 10567-10574. PMI: 17652384

Liu J, Zheng Q, Deng Y, Li Q, Kallenbach NR, Lu M (2007) Conformational specificity of the lac repressor coiled-coil tetramerization domain. Biochemistry 46: 14951-14959. PMI: 18052214

Ketas TJ, Schader SM, Zurita J, Teo E, Polonis V, Lu M, Klasse PJ, Moore JP (2007) Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology 364: 431-440. PMI: 17428517

Deng Y, Zheng Q, Liu J, Cheng CS, Kallenbach NR, Lu M (2007) Self-assembly of coiled-coil tetramers in the 1.40 A structure of a leucine-zipper mutant. Protein Sci 16: 323-328. PMI: 17189475

Deng Y, Zheng Q, Ketas TJ, Moore JP, Lu M (2007) Protein design of a bacterially expressed HIV-1 gp41 fusion inhibitor. Biochemistry 46: 4360-4369. PMI: 17371053

Zheng Q, Deng Y, Liu J, van der Hoek L, Berkhout B, Lu M (2006) Core structure of S2 from the human coronavirus NL63 spike glycoprotein. Biochemistry 45: 15205-15215. PMI: 17176042

Liu J, Zheng Q, Deng Y, Kallenbach NR, Lu M (2006) Conformational transition between four and five-stranded phenylalanine zippers determined by a local packing interaction. J Mol Biol 361: 168-179. PMI: 16828114

Liu J, Zheng Q, Deng Y, Cheng CS, Kallenbach NR, Lu M (2006) A seven-helix coiled coil. Proc Natl Acad Sci U S A 103: 15457-15462. PMI: 17030805

Liu J, Deng Y, Zheng Q, Cheng CS, Kallenbach NR, Lu M (2006) A parallel coiled-coil tetramer with offset helices. Biochemistry 45: 15224-15231. PMI: 17176044

Deng Y, Liu J, Zheng Q, Yong W, Lu M (2006) Structures and polymorphic interactions of two heptad-repeat regions of the SARS virus S2 protein. Structure 14: 889-899. PMI: 16698550

Deng Y, Liu J, Zheng Q, Eliezer D, Kallenbach NR, Lu M (2006) Antiparallel four-stranded coiled coil specified by a 3-3-1 hydrophobic heptad repeat. Structure 14: 247-255. PMI: 16472744

Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP (2005) Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438: 99-102. PMI: 16258536

Liu J, Yong W, Deng Y, Kallenbach NR, Lu M (2004) Atomic structure of a tryptophan-zipper pentamer. Proc Natl Acad Sci U S A 101: 16156-16161. PMI: 15520380

Dai J, Liu J, Deng Y, Smith TM, Lu M (2004) Structure and protein design of a human platelet function inhibitor. Cell 116: 649-659. PMI: 15006348






C.V.


Dr. Lu received his Ph.D. in biophysical chemistry in 1990 from New York University, where he worked with Neville R. Kallenbach. He did postdoctoral work with Nancy Kleckner at Harvard University and with Peter S. Kim at the Whitehead Institute for Biomedical Research of Massachusetts Institute of Technology. Dr. Lu joined Weill Cornell Medical College in 1996 as assistant professor of biochemistry and became associate professor in 2001 and professor in 2006. He joined UMDNJ (now Rutgers, The State University of New Jersey) as professor of microbiology and molecular genetics in 2010.


 
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