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Longhu Zhou

Publications and source records attributed to Longhu Zhou.

8 recordsLinked to original sources
PubMed2006

Delivery of 2-5A cargo into living cells using the Tat cell penetrating peptide: 2-5A-tat.

2',5'-Oligoadenylate tetramer (2-5A) has been chemically conjugated to short HIV-1 Tat peptides to provide 2-5A-tat chimeras. Two different convergent synthetic approaches have been employed to provide such 2-5A-tat bioconjugates. One involved generation of a bioconjugate through reaction of a cysteine terminated Tat peptide with a alpha-chloroacetyl derivative of 2-5A. The second synthetic strategy was based upon a cycloaddition reaction of an azide derivative of 2-5A with a Tat peptide bearing an alkyne function. Either bioconjugate of 2-5A-tat was able to activate human RNase L. The union of 2-5A and Tat peptide provided an RNase L-active chimeric nucleopeptide with the ability to be taken up by cells by virtue of the Tat peptide and to activate RNase L in intact cells. This strategy provides a valuable vehicle for the entry of the charged 2-5A molecule into cells and may provide a means for targeted destruction of HIV RNA in vivo.

Adenine Nucleotides↗
PubMed2006

Toward orthopoxvirus countermeasures: a novel heteromorphic nucleoside of unusual structure.

Two privileged drug scaffolds have been hybridized to create the novel heteromorphic nucleoside 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4(1H,3H)-dione (2). Compound 2 inhibited the replication of two orthopoxviruses, vaccinia virus (VV) (EC(50) = 4.6 +/- 2.0 microM), and cowpox virus (CV) (EC(50) = 2.0 +/- 0.3 microM). Compound 2 exhibited reduced activity against a thymidine kinase (TK) negative strain of CV, implying a requirement for 5'-monophosphorylation for antiorthopoxvirus activity. Compound 2 was efficiently phosphorylated by VV TK, establishing that VV TK is more promiscuous than previously believed.

Antiviral Agents↗
PubMed2006

5-(Dimethoxymethyl)-2'-deoxyuridine: a novel gem diether nucleoside with anti-orthopoxvirus activity.

To provide potential new leads for the treatment of orthopoxvirus infections, the 5-position of the pyrimidine nucleosides have been modified with a gem diether moiety to yield the following new nucleosides: 5-(dimethoxymethyl)-2'-deoxyuridine (2b), 5-(diethoxymethyl)-2'-deoxyuridine (3b), 5-formyl-2'-deoxyuridine ethylene acetal (4b), and 5-formyl-2'-deoxyuridine propylene acetal (5b). These were evaluated in human foreskin fibroblast cells challenged with the vaccinia virus or cowpox virus. Of the four gem diether nucleosides, only the dimethyl gem diether congener showed significant antiviral activity against both viruses. This antiviral activity did not appear to be related to the decomposition to the 5-formyl-2'-deoxyuridine, which was itself devoid of anti-orthopoxvirus activity in these assays. Moreover, at the pH of the in vitro assays, 2b was very stable with a decomposition (to aldehyde) half-life of >15 d. The anti-orthopoxvirus activity of pyrimidine may be favored by the introduction of hydrophilic moieties to the 5-position side chain.

Animals↗
PubMed2005

Synthesis and antiviral activities of 1,2,3-triazole functionalized thymidines: 1,3-dipolar cycloaddition for efficient regioselective diversity generation.

Efficient regioselective synthesis of nucleoside conjugates was achieved by cycloaddition reaction of azides and alkynes using sodium ascorbate/ CuSO4 system as a catalyst. These 16 novel thymidine analogues were obtained in excellent yields (75-100%), employing mild reaction conditions with a broad scope of structural modification. For the compounds tested, no specific antiviral effects could be witnessed against a broad range of viruses.

Anti-HIV Agents↗
PubMedDate not supplied

Endowing RNase H-inactive antisense with catalytic activity: 2-5A-morphants.

A convergent synthetic approach was used to conjugate 2',5'-oligoadenylate (2-5A, p5'A2' [p5'A2'](n)()p5'A) to phosphorodiamidate morpholino oligomers (morphants). To provide requisite quantities of 2-5A starting material, commercially and readily available synthons for solid-phase synthesis were adapted for larger scale solution synthesis. Thus, the tetranucleotide 5'-phosphoryladenylyl(2'-->5')adenylyl(2'-->5')adenylyl(2'-->5')adenosine (p5'A2'p5'A2'](2)p5'A2', tetramer 2-5A, 9) was synthesized starting with 2',3'-O-dibenzoyl-N(6),N(6)-dibenzoyl adenosine prepared from commercially available 5'-O-(4-monomethoxytrityl) adenosine. Coupling with N(6)-benzoyl-5'-O-(4,4'-dimethoxytrityl)-3'-O-(tert-butyldimethylsilyl) adenosine-2'-(N,N-diisopropyl-2-cyanoethyl)phosphoramidite, followed by oxidization and deprotection, generated 5'-deprotected dimer 2-5A. Similar procedures lengthened the chain to form protected tetramer 2-5 A. The title product 9 p5'A(2'p5'A)(3) (tetramer 2-5A) was obtained through phosphorylation of the terminal 5'-hydroxy of the protected tetramer and removal of remaining protecting groups using concentrated ammonium hydroxide-ethanol (3:1, v/v) at 55 degrees C and tetrabutylammonium fluoride (TBAF) in THF at room temperature, respectively. The 2-5A-phosphorodiamidate morpholino antisense chimera 11 (2-5A-morphant) was synthesized by covalently linking an aminolinker-functionalized phosphorodiamidate morpholino oligomer with periodate oxidized 2-5A tetramer (p5'A2'[p5'A2'](2)p5'A). The resulting Schiff base was reduced with cyanoborohydride thereby transforming the ribose of the 2'-terminal nucleotide of 2-5A N-substituted morpholine. RNase L assays demonstrated that this novel 2-5A-antisense chimera had significant biological activity, thereby providing another potential tool for RNA ablation.

Antineoplastic Agents↗