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Featured researches published by Dong Yu.


Biochemical Pharmacology | 1995

Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration

Sudhir Agrawal; Xueshu Zhang; Zhihong Lu; Hui Zhao; Jeffrey M. Tamburin; Jieming Van; Hongying Cai; Robert B. Diasio; Ivan Habus; Zhiwei Jiang; Radhakrishnan P. Iyer; Dong Yu; Ruiwen Zhang

In vivo stability and oral bioavailability of an oligodeoxynucleotide phosphorothioate containing segments of 2-O-methyloligoribonucleotide phosphorothioates at both the 3- and 5-ends (hybrid oligonucleotide) were studied. A 25-mer 35S-labeled hybrid oligonucleotide was administered to rats by gavage at a dose of 50 mg/kg body weight. HPLC analysis revealed that this hybrid oligonucleotide was stable in the gastrointestinal tract for up to 6 hr following oral administration. Radioactivity associated with the hybrid oligonucleotide was detectable in portal venous plasma, systemic plasma, various tissues, and urine. Intact hybrid oligonucleotide was detected, by HPLC analysis, in portal venous plasma, systemic plasma, and various tissues. The majority of the radioactivity in urine was associated with degradative products with lower molecular weights, but the intact form was also detected. In summary, the hybrid oligonucleotide was absorbed intact through the gastrointestinal tract, indicating the possibility of oral administration of oligonucleotides, a finding that may be important in the development of antisense oligonucleotides as therapeutic agents.


Bioorganic & Medicinal Chemistry | 2001

Effect of chemical modifications of cytosine and guanine in a cpg-motif of oligonucleotides: structure–immunostimulatory activity relationships

Ekambar R. Kandimalla; Dong Yu; Qiuyan Zhao; Sudhir Agrawal

Oligodeoxynucleotides containing unmethylated CpG-motifs stimulate the innate immune system, including inducing B-cell proliferation and cytokine production. However, the mechanism of immunostimulation by CpG-oligonucleotides and the precise structural requirements and specific functional groups of cytosine and guanine necessary for recognition of and interaction with protein/receptor factors that are responsible for immune stimulation have not been elucidated. We sought to understand the critical role of each functional group of the cytosine and guanine moieties in a CpG-motif in inducing immunostimulatory activity. To this end, we examined structure-immunostimulatory activity relationships of phosphorothioate oligodeoxynucleotides (PS-oligos) containing YpG- and CpR-motifs (Y and R stand for pyrimidine and purine analogues, respectively). The PS-oligos containing a YpG-motif in which the natural deoxycytidine was replaced with deoxy-5-hydroxycytidine or deoxy-N4-ethylcytidine showed immunostimulatory activity. Substitution of deoxycytidine with a deoxy-5-methylisocytidine, deoxyuridine, or deoxy-P-base-nucleoside in the YpG-motif completely abolished the immunostimulatory activity, similar to the results observed with deoxy-5-methylcytidine. In the case of PS-oligos containing a CpR-motif, 7-deazaguanine substitution for natural guanine showed immunostimulatory activity similar to that of a parent PS-oligo. These studies suggest that the 2-keto, 3-imino and 4-amino groups of cytosine, and the 1-imino, 2-amino and 6-keto groups of guanine in a CpG-motif are important for the immunostimulatory activity of CpG-PS-oligos. The absence of N7 on guanine of the CpG-motif does not affect immunostimulatory activity significantly. These studies suggest that it is possible to develop YpG- and CpR-motifs as an alternative to CpG-motifs in PS-oligos for immunostimulatory studies.


Biochemical Pharmacology | 1995

In vivo stability, disposition and metabolism of a "hybrid" oligonucleotide phosphorothioate in rats

Ruiwen Zhang; Zhihong Lu; Hui Zhao; Xueshu Zhang; Robert B. Diasio; Ivan Habus; Zhiwei Jiang; Radhakrishnan P. Iyer; Dong Yu; Sudhir Agrawal

Oligodeoxynucleotide phosphorothioates containing segments of 2-O-methyloligoribonucleotide phosphorothioates at both 3- and 5-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 +/- 3.21% (mean +/- SD) of the administered dose excreted within 24 hr and 38.13 +/- 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 +/- 0.13% of the administered dose excreted over 24 hr and 6.74 +/- 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined oligodeoxynucleotide phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.


Bioorganic & Medicinal Chemistry Letters | 2000

Accessible 5′-end of CpG-containing Phosphorothioate Oligodeoxynucleotides is essential for immunostimulatory activity

Dong Yu; Qiuyan Zhao; Ekambar R. Kandimalla; Sudhir Agrawal

In our ongoing efforts to decipher the sequence and structural requirements in the flanking region of the CpG motif in phosphorothioate oligodeoxynucleotides (PS-oligos), we have examined the requirement of free 5- and 3-ends of PS-oligos on immune stimulation. Our model studies using 3-3-linked (containing two free 5-ends) and 5-5-linked (containing two free 3-ends) CpG-containing PS-oligos demonstrate that immunostimulatory activity is significantly reduced when the 5-end of the PS-oligo is not accessible, rather than the 3-end, suggesting that the 5-end plays a critical role in immunostimulatory activity.


Biochemical and Biophysical Research Communications | 2003

CpG penta- and hexadeoxyribonucleotides as potent immunomodulatory agents.

Lakshmi Bhagat; Fu-Gang Zhu; Dong Yu; Jimmy X. Tang; Hui Wang; Ekambar R. Kandimalla; Ruiwen Zhang; Sudhir Agrawal

We demonstrate a new design for immunomodulatory CpG DNA containing two sequences each with as few as five or six-nucleotides joined together via 3()-3() linkers. These do not require the -PuPu(Py)CGPyPy- hexameric motif generally found essential for CpG DNA immune stimulation. These novel, short-immunomers show potent immunostimulatory activity manifested by IL-12 and IL-6 secretion in murine spleen cell and PBMC cultures and splenomegaly in vivo. Short-immunomers show strong activation of NF-kappaB and stress-activated signaling pathways and induce cytokines in J774 cell cultures. The same sequences also induce cytokines in healthy human PBMC cultures whereas conventional CpG DNA requires different optimal sequences for murine and human immune cells. Additionally, short-immunomers inhibit IL-5 secretion and induce IFN-gamma secretion in conalbumin-sensitized mouse spleen cell cultures, suggesting reversal of established Th2 responses to Th1 type responses. Short-immunomer also inhibits growth of MCF-7 human tumor xenograft in nude mice. This is the first report of activity with such short DNA sequences and also of sequences lacking hexameric motifs proposed in earlier studies.


Biochemical and Biophysical Research Communications | 2003

Secondary structures in CpG oligonucleotides affect immunostimulatory activity.

Ekambar R. Kandimalla; Lakshmi Bhagat; Yanping Cong; Rajendra K. Pandey; Dong Yu; Qiuyan Zhao; Sudhir Agrawal

Oligodeoxynucleotides containing CpG dinucleotides in specific sequence contexts activate the vertebrate immune system. Our previous studies showed that the 5()-end of a CpG oligonucleotide should be accessible for receptor recognition and subsequent immune stimulation. Activity is abrogated if this end is blocked by joining two CpG oligos through 5()-5() linkage. It was not known whether a similar effect would arise from secondary structures at either end of a CpG oligo, such as hairpin loops or terminal dimers. In the present study we found that 5()-terminal secondary structures affect activity significantly more than those at the 3()-end. The need for an open 5()-end suggests that the receptor responsible for immune stimulation reads the DNA sequence from this end. These results may also provide insights to place CpG motifs appropriately in DNA vaccines to induce additional Th1 type responses.


Bioorganic & Medicinal Chemistry Letters | 1999

Site of chemical modifications in CpG containing phosphorothiate oligodeoxynucleotide modulates its immunostimulatory activity

Qiuyan Zhao; Dong Yu; Sudhir Agrawal

Phosphorothioate oligodeoxynucleotides containing CpG motifs have immunostimulatory activity. Appropriate substitution of deoxynucleosides in the flanking region of CpG-containing phosphorothioate oligodeoxynucleotides with 2-O-methylribonucleosides results in significant decreases or increases in their immunostimulatory activities. The results provide insights in how to chemically modify phosphorothioate oligodeoxynucleotides containing CpG motifs to suppress or enhance their immunostimulatory activity for different therapeutic uses.


Biochemical and Biophysical Research Communications | 2002

Potent CpG oligonucleotides containing phosphodiester linkages: in vitro and in vivo immunostimulatory properties

Dong Yu; Fu-Gang Zhu; Lakshmi Bhagat; Hui Wang; Ekambar R. Kandimalla; Ruiwen Zhang; Sudhir Agrawal

Bacterial and synthetic DNAs, containing CpG dinucleotides in specific sequence contexts, activate the vertebrate immune system. Unlike phosphorothioate (PS) CpG DNAs, phosphodiester (PO) CpG DNAs require either palindromic sequences and/or poly(dG) sequences at the 3()-end for activity. Here, we report PO-immunomers having two PO-CpG DNA molecules joined through their 3()-ends. These PO-imunomers permitted us, for the first time, to assess immunostimulatory properties of PO-CpG DNAs in vitro and in vivo without the need for palindromic and/or poly(dG) sequences. In medium containing 10% fetal bovine serum, PO-immunomers were more resistant than PO-CpG DNAs to nucleases. Compared to PS-CpG DNA in BALB/c and C3H/HeJ mice spleen cell culture assays, PO-immunomers showed increased IL-12 secretion and minimal amounts of IL-6 secretion. PO-immunomers activated NF-kappa B and induced cytokine secretion in J774 cell cultures. In addition, PO-immunomers showed antitumor activity in nude mice bearing human breast (MCF-7) and prostate (DU145) cancer xenografts.


Bioorganic & Medicinal Chemistry | 2000

Stereo-enriched phosphorothioate oligodeoxynucleotides: synthesis, biophysical and biological properties.

Dong Yu; Ekambar R. Kandimalla; Allysen Roskey; Qiuyan Zhao; Lihong Chen; Jiangdong Chen; Sudhir Agrawal

Stereo-enriched [Rp] and [Sp]-phosphorothioate oligodeoxynucleotides are synthesized using oxazaphospholidine derivatized monomers. Three different designs of phosphorothioate oligodeoxynucleotides (PS-oligos), (i) stereo-enriched all-[Rp] or all-[Sp] PS-linkages, (ii) stereo-random mixture of PS-linkages, and (iii) segments containing certain number of stereo-enriched [Rp] and [Sp] PS-linkages ([Sp-Rp-Sp] or [Rp-Sp-Rp]), have been studied. Thermal melting studies of these PS-oligos with RNA complementary strands showed that the binding affinities are in the order [Rp] > [Sp-Rp-Sp]-[Rp-Sp-Rp] > stereo-random > [Sp]. Circular dichroism (CD) studies suggest that the stereochemistry of the PS-oligo does not affect the global conformation of the duplex. The in vitro nuclease stability of these PS-oligos is in the order [Sp] > [Sp-Rp-Sp] > stereo-random > [Rp]. The RNase H activation is in the order [Rp] > stereo-random > [Rp-Sp-Rp] > [Sp] > [Sp-Rp-Sp]. Studies in a cancer cell line of PS-oligos targeted to MDM2 mRNA showed that all oligos had similar biological activity under the experimental conditions employed. Protein- and enzyme-binding studies showed insignificant stereo-dependent binding to proteins. The [Sp] and [Sp-Rp-Sp] chimeric and stereo-random PS-oligos that contained a CpG motif showed higher cell proliferation than [Rp] PS-oligo of the same sequence.


Bioorganic & Medicinal Chemistry Letters | 2000

Immunostimulatory activity of CpG containing phosphorothioate oligodeoxynucleotide is modulated by modification of a single deoxynucleoside.

Qiuyan Zhao; Dong Yu; Sudhir Agrawal

Phosphorothioate oligodeoxynucleotides (PS-oligos) containing the CpG motif have immunostimulatory properties. Our earlier study had shown that the immunostimulatory activity of PS-oligos containing the CpG motif can be modulated by incorporation of 2-O-methylribonucleosides (Zhao, Q.; Yu, D.; Agrawal, S. Bioorg. Med. Chem. Lett. 1999, 9, 3453). Here we show that the immunostimulatory activity of a PS-oligo containing a CpG motif can be modulated by substitution of a single deoxynucleoside at specific sites with either 2-O-methylribonucleoside or 3-O-methylribonucleoside in the flanking region to CpG motif. Furthermore, substitution of deoxynucleosides with 2-O-methoxyethoxyribonucleosides also results in modulating immunostimulatory activity of PS-oligos.

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Ruiwen Zhang

Texas Tech University Health Sciences Center

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Hui Wang

Chinese Academy of Sciences

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Hui Zhao

University of Alabama at Birmingham

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Xueshu Zhang

University of Alabama at Birmingham

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Zhihong Lu

University of Alabama at Birmingham

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