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Rational Drug Design Targeting Adenylation Enzymes
Salicyl-AMS, a novel adenylation inhibitor developed by rational drug design
Recent evidence suggests that natural products are much more than simply agents of “microbial warfare” and actually play critical roles in bacterial pathogenesis and communication. In particular, non-ribosomal peptide (NRP) natural products have been identified as key players in bacterial iron uptake, biofilm formation, commensalism, and virulence. Thus, small molecule inhibition of NRP biosynthesis provides a powerful means to study the biological roles of these natural products and a potential avenue to develop novel antibiotics. Detailed mechanistic insights into NRP biosynthesis, developed primarily from the perspectives of fundamental interest and engineered biosynthesis, can be leveraged to design such inhibitors.
Crystal structure of the SUMO E1 enzyme with SUMO-AVSN, a chemical probe developed by rational drug design
In collaboration with Prof. Luis E. N. Quadri at Cornell-Weill Medical College, we have developed a number of small molecule inhibitors of NRP biosynthesis using natural product-inspired mechanism- and structure-based design. These compounds target enzymes that catalyze key adenylation reactions in the biosyntheses of iron-chelating siderophores and mycobacterial phenolic glycolipids. We are now advancing these compounds toward preclinical evaluation in animal infection models with Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, the etiologic agent of the plague. In collaboration with Prof. Peter J. Tonge at Stony Brook University, we have also developed related inhibitors of menaquinone biosynthesis enzymes as a new class of potential antibiotics.
Recently, in collaboration with Prof. Christopher D. Lima at MSKCC, we have used related strategies to develop semisynthetic, mechanism-based protein inhibitors of ubiquitin/ubiquitin-like E1 activation enzymes that regulate diverse biological processes in eukaryotes. This work has revealed striking conformational changes that occur during catalysis and provides new mechanistic insights that may be useful in drug discovery targeting these enzymes.
Publications
Olsen, S. K.; Capili. A. D.; Lu, X.; Tan, D. S.*; Lima, C. D.* “Active site remodelling accompanies thioester bond formation in the SUMO E1.” Nature 2010, 463, 906-912.
[ Abstract | PDF | Supporting Info | PMC ]
Highlighted in Nature, Chem. Eng. News, Nat. Rev. Mol. Cell Biol., Nat. Chem. Biol., Structure, ACS Chem. Biol., and Faculty of 1000 Biology
Lu, X.; Olsen, S. K.; Capili, A. D.; Cisar, J. S.; Lima, C. D.*; Tan, D. S.* “Designed semisynthetic protein inhibitors of Ub/Ubl E1 activating enzymes.” J. Am. Chem. Soc. 2010, 132, 1748-1749.
[ Abstract | PDF | Supporting Info | PMC ]
Highlighted in Chem. Eng. News, Nat. Rev. Mol. Cell Biol., Nat. Chem. Biol., ACS Chem. Biol., and Faculty of 1000 Biology
Lu, X.; Zhang, H.; Tonge, P. J.*; Tan, D. S.* “Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis.” Bioorg. Med. Chem. Lett. 2008, 18, 5963-5966.
[ Abstract | PDF | Supporting Info | PMC ]
Cisar, J. S.; Tan, D. S.* “Small molecule inhibition of microbial natural product biosynthesis - An emerging antibiotic strategy.” Chem. Soc. Rev. 2008, 37, 1320-1329.
[ Abstract | PDF | PMC ]
Ferreras, J. A.; Stirrett, K. L.; Lu, X.; Ryu, J.-S.; Soll, C. E.; Tan, D. S.; Quadri, L. E. N.* “Mycobacterial phenolic glycolipid virulence factor biosynthesis: Mechanism and small-molecule inhibition of polyketide chain initiation.” Chem. Biol. 2008, 15, 51-61.
[ Abstract | PDF | Supporting Info | PMC ]
Highlighted in Chem. Biol.
Cisar, J. S.; Ferreras, J. A.; Soni, R. K.; Quadri, L. E. N.*; Tan, D. S.* “Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules.” J. Am. Chem. Soc. 2007, 129, 7752-7753.
[ Abstract | PDF | Supporting Info | PMC ]
Highlighted in Faculty of 1000 Biology
Ferreras, J. A.; Ryu, J.-S.; Di Lello, F.; Tan, D. S.*, Quadri, L. E. N.* “Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis.” Nature Chem. Biol. 2005, 1, 29-32.
[ Abstract | PDF | Supporting Info ]
Highlighted in Nature, Nat. Chem. Biol., Chem. Eng. News, and Mercosur Económico
News Articles
02/22/2010
Activation of Protein Tags: Enzymology: To prepare biological labels for attachment, E1 enzymes dramatically remodel themselves
Chemical & Engineering News
In a tour de force chemical, structural, and mechanistic study that took five years, researchers have solved a long-standing mystery in a Nobel Prize-winning field of research-they have shown how E1 enzymes activate ubiquitin and related proteins to tag other proteins. [Full text]
02/18/2010
Structural Biology: Transformative Encounters
Nature
Researchers have met the challenge of capturing transient states of the SUMO E1 activating enzyme. Their pictures show radically different crystal structures for two of the steps in this enzyme's activity. [Full text]
08/18/2008
From Peptides to Polymers: Molecular probes for biological investigation
NYAS eBriefing
Chemical biologists seek to design new chemical tools for use in research and medicine. Their search is predicated on the incredible diversity of chemical structures, both natural and otherwise. This diversity was well represented at the Chemical Biology Discussion Group's Special Year-End Meeting, held June 2, 2008.
[Overview (free) | Meeting report (membership req'd)]
Justin Cisar's seminar: Inhibition of Nonribosomal Peptide Synthetase Amino Acid Adenylation Domains
[Video (membership req'd)]
12/27/2007
New Drug Targets May Fight Tuberculosis and Other Bacterial Infections in Novel Way
Weill Cornell News
Research into “virulence factors” expands war against infectious disease beyond antibiotics, Weill Cornell researchers say. [Full text]
09/01/2005
New Potential Antibiotic Inhibits Bacterial Growth
MSKCC Center News
Memorial Sloan-Kettering Cancer Center and Cornell University researchers have synthesized a molecule impeding the growth of two harmful bacteria: M. tuberculosis, estimated to infect one-third of the world's population, and Y. pestis, the cause of pneumonic and bubonic plague. [Full text]
06/13/2005
Investigadores elaboran compuesto para combatir bacterias de la tuberculosis y la peste negra
Mercosur Económico
Investigadores de dos prestigiosas instituciones de Nueva York…desarrollaron un compuesto capaz de combatir bacterias -de la tuberculosis y de la peste negra- y permitir la elaboración de nuevas drogas contra una enfermedad que afecta a un tercio de la población mundial -la tuberculosis- y otra en condiciones de ser empleada como arma biológica en bioterrorismo -la peste negra-. [Full text]
05/30/2005
A New Way To Fight Bacteria: Inhibitor blocks biosynthesis of key bacterial iron-scavenging agent
Chemical & Engineering News
A novel strategy for fighting bacterial infections has been demonstrated: blocking bacterial biosynthesis of siderophores, compounds that make it possible for certain bacteria to obtain iron, which they require to grow and to cause disease. [Full text]
05/26/2005
Chemical Biology: Ironing out bugs
Nature
Researchers from Cornell University and the Memorial Sloan-Kettering Cancer Center in New York have devised a molecule that binds to and inhibits enzymes involved in siderophore synthesis. The compound successfully reduces the growth of both Mycobacterium tuberculosis and Yersinia pestis under iron-poor in vitro conditions. [Full text]
