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Dive into the research topics where Yongcheng Song is active.

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Featured researches published by Yongcheng Song.


Science | 2008

A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

Chia I. Liu; George Y. Liu; Yongcheng Song; Fenglin Yin; Mary E. Hensler; Wen-Yih Jeng; Victor Nizet; Andrew H.-J. Wang; Eric Oldfield

Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration ∼100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor–based therapy against S. aureus.


Journal of the American Chemical Society | 2009

Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.

Yonghui Zhang; Rong Cao; Fenglin Yin; Michael P. Hudock; Rey-Ting Guo; Kilannin Krysiak; Sujoy Mukherjee; Yi Gui Gao; Howard Robinson; Yongcheng Song; Joo Hwan No; Kyle Bergan; Annette Leon; Lauren M. Cass; Amanda Goddard; Ting Kai Chang; Fu Yang Lin; Ermond van Beek; Socrates E. Papapoulos; Andrew H.-J. Wang; Tadahiko Kubo; Mitsuo Ochi; Dushyant Mukkamala; Eric Oldfield

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases

Rey-Ting Guo; Rong Cao; Po-Huang Liang; Tzu-Ping Ko; Tao Hsin Chang; Michael P. Hudock; Wen-Yih Jeng; Cammy K.-M. Chen; Yonghui Zhang; Yongcheng Song; Chih-Jung Kuo; Fenglin Yin; Eric Oldfield; Andrew H.-J. Wang

Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.


Journal of the American Chemical Society | 2008

NMR Investigations of the Static and Dynamic Structures of Bisphosphonates on Human Bone: a Molecular Model

Sujoy Mukherjee; Yongcheng Song; Eric Oldfield

We report the results of an investigation of the binding of a series of bisphosphonate drugs to human bone using 2H, 13C, 15N, and 31P nuclear magnetic resonance spectroscopy. The 31P NMR results show that the bisphosphonate groups bind irrotationally to bone, displacing orthophosphate from the bone mineral matrix. Binding of pamidronate is well described by a Langmuir-like isotherm, from which we deduce an approximately 30-38 A2 surface area per pamidronate molecule and a deltaG = -4.3 kcal mol(-1). TEDOR of [13C3, 15N] pamidronate on bone shows that the bisphosphonate binds in a gauche [N-C(1)] conformation. The results of 31P as well as 15N shift and cross-polarization measurements indicate that risedronate binds weakly, since it has a primarily neutral pyridine side chain, whereas zoledronate (with an imidazole ring) binds more strongly, since the ring is partially protonated. The results of 2H NMR measurements of side-chain 2H-labeled pamidronate, alendronate, zoledronate, and risedronate on bone show that all side chains undergo fast but restricted motions. In pamidronate, the motion is well simulated by a gauche+/gauche- hopping motion of the terminal -CH2-NH3(+) group, due to jumps from one anionic surface group to another. The results of double-cross polarization experiments indicate that the NH3(+)-terminus of pamidronate is close to the bone mineral surface, and a detailed model is proposed in which the gauche side-chain hops between two bone PO4(3-) sites.


Journal of Immunology | 2008

Photoaffinity Antigens for Human γδ T Cells

Ghanashyam Sarikonda; Hong Wang; Kia Joo Puan; Xiao hui Liu; Hoi K. Lee; Yongcheng Song; Mark D. Distefano; Eric Oldfield; Glenn D. Prestwich; Craig T. Morita

Vγ2Vδ2 T cells comprise the major subset of peripheral blood γδ T cells in humans and expand during infections by recognizing small nonpeptide prenyl pyrophosphates. These molecules include (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP), a microbial isoprenoid intermediate, and isopentenyl pyrophosphate, an endogenous isoprenoid intermediate. Recognition of these nonpeptide Ags is mediated by the Vγ2Vδ2 T cell Ag receptor. Several findings suggest that prenyl pyrophosphates are presented by an Ag-presenting molecule: contact between T cells and APC is required, the Ags do not bind the Vγ2Vδ2 TCR directly, and Ag recognition is abrogated by TCR mutations in CDRs distant from the putative Ag recognition site. Identification of the putative Ag-presenting molecule, however, has been hindered by the inability to achieve stable association of nonpeptide prenyl pyrophosphate Ags with the presenting molecule. In this study, we show that photoaffinity analogues of HMBPP, meta/para-benzophenone-(methylene)-prenyl pyrophosphates (m/p-BZ-(C)-C5-OPP), can crosslink to the surface of tumor cell lines and be presented as Ags to γδ T cells. Mutant tumor cell lines lacking MHC class I, MHC class II, β2-microglobulin, and CD1, as well as tumor cell lines from a variety of tissues and individuals, will all crosslink to and present m-BZ-C5-OPP. Finally, pulsing of BZ-(C)-C5-OPP is inhibited by isopentenyl pyrophosphate and an inactive analog, suggesting that they bind to the same molecule. Taken together, these results suggest that nonpeptide Ags are presented by a novel-Ag-presenting molecule that is widely distributed and nonpolymorphic, but not classical MHC class I, MHC class II, or CD1.


Journal of Medicinal Chemistry | 2009

Phosphonosulfonates Are Potent, Selective Inhibitors of Dehydrosqualene Synthase and Staphyloxanthin Biosynthesis in Staphylococcus aureus

Yongcheng Song; Fu Yang Lin; Fenglin Yin; Mary E. Hensler; Carlos A.Rodrígues Poveda; Dushyant Mukkamala; Rong Cao; Hong Wang; Craig T. Morita; Dolores Gonzalez Pacanowska; Victor Nizet; Eric Oldfield

Staphylococcus aureus produces a golden carotenoid virulence factor called staphyloxanthin (STX), and we report here the inhibition of the enzyme, dehydrosqualene synthase (CrtM), responsible for the first committed step in STX biosynthesis. The most active compounds are halogen-substituted phosphonosulfonates, with K(i) values as low as 5 nM against the enzyme and IC(50) values for STX inhibition in S. aureus as low as 11 nM. There is, however, only a poor correlation (R(2) = 0.27) between enzyme and cell pIC(50) (= -log(10) IC(50)) values. The ability to predict cell from enzyme data improves considerably (to R(2) = 0.72) with addition of two more descriptors. We also investigated the activity of these compounds against human squalene synthase (SQS), as a counterscreen, finding several potent STX biosynthesis inhibitors with essentially no squalene synthase activity. These results open up the way to developing potent and selective inhibitors of an important virulence factor in S. aureus, a major human pathogen.


Journal of Medicinal Chemistry | 2009

Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results.

Yongcheng Song; Chia I. Liu; Fu-Yang Lin; Joo Hwan No; Mary E. Hensler; Yi-Liang Liu; Wen-Yih Jeng; Jennifer Low; George Y. Liu; Victor Nizet; Andrew H.-J. Wang; Eric Oldfield

The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K(i) values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC(50) = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.


Bioorganic & Medicinal Chemistry | 2008

Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation.

Yongcheng Song; Julian M. W. Chan; Zev Tovian; Aaron M. Secrest; Eva Nagy; Kilannin Krysiak; Kyle Bergan; Michael A. Parniak; Eric Oldfield

We report the results of an investigation of the inhibition of the ATP-mediated HIV-1 reverse transcriptase catalyzed phosphorolysis in vitro of AZT from AZT-terminated DNA primers by a series of 42 bisphosphonates. The four most active compounds possess neutral, halogen-substituted phenyl or biphenyl sidechains and have IC(50) values < 1 microM in excision inhibition assays. Use of two comparative molecular similarity analysis methods to analyze these inhibition results yielded a classification model with an overall accuracy of 94%, and a regression model having good accord with experiment (q(2)=0.63, r(2)=0.91), with the experimental activities being predicted within, on average, a factor of 2. The most active species had little or no toxicity against three human cell lines (IC(50)(avg) > 200 microM). These results are of general interest since they suggest that it may be possible to develop potent bisphosphonate-based AZT-excision inhibitors with little cellular toxicity, opening up a new route to restoring AZT sensitivity in otherwise resistant HIV-1 strains.


Journal of Medicinal Chemistry | 2004

Quantitative Structure−Activity Relationships for γδ T Cell Activation by Bisphosphonates

John M. Sanders; Subhash Ghosh; Julian M. W. Chan; Gary A. Meints; Hong Wang; Amy M. Raker; Yongcheng Song; Alison Colantino; Agnieszka Burzyńska; Paweł Kafarski; Craig T. Morita; Eric Oldfield


Journal of the American Chemical Society | 2006

Solid-State NMR, Crystallographic, and Computational Investigation of Bisphosphonates and Farnesyl Diphosphate Synthase−Bisphosphonate Complexes

Junhong Mao; Sujoy Mukherjee; Yong Zhang; Rong Cao; John M. Sanders; Yongcheng Song; Yonghui Zhang; Gary A. Meints; Yi Gui Gao; Dushyant Mukkamala; Michael P. Hudock; Eric Oldfield

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Yonghui Zhang

University of California

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Craig T. Morita

Roy J. and Lucille A. Carver College of Medicine

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Rey-Ting Guo

Chinese Academy of Sciences

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Wen-Yih Jeng

National Cheng Kung University

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George Y. Liu

University of California

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Victor Nizet

University of Illinois at Urbana–Champaign

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