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Biomedical subjects

P F Torrence

Publications and source records attributed to P F Torrence.

At least 145 records · Page 8Linked to original sources
PubMed1975

Inhibition of oncornavirus functions by 2'-azido polynucleotides.

The 2'-azido analogs of poly(U) and poly(C), poly(dUz) [poly(2'-azido-2'-deoxyuridylic acid)], and poly-(dCz [poly(2'-azido-2'-deoxycytidylic acid)], were found to inhibit the RNA-directed DNA polymerase (reverse transcriptase) activity of murine leukemia (Moloney, Rauscher) and sarcoma (Moloney) virus, and feline leukemia (Theilen) and sarcoma (Gardner) virus, while under the same conditions the unsubstituted parent compounds failed to do so. In addition, poly(dUz) and poly(dCz) inhibited the replication of exogenous murine sarcoma virus (Moloney) in nontransformed cells (as assessed by an infectious center assay), but poly(dUz) failed to suppress the formation of endogenous sarcoma and leukemia viruses in transformed cell lines (MO-P, JLSV5). In these same cells, poly(dUz) failed to inhibit the multiplication of vesicular stomatitis virus. These data add further strength to the contention that reverse transcriptase is necessary for the productive infection and transformation of normal cells by oncornaviruses but is not essential maintenance of this transformed state and the continuous production of new viruses particles by these transformed cells.

Animals↗
PubMed1975

Structural features of double-stranded polyribonucleotides required for immunological specificity and interferon induction.

Purified antibody to poly(adenylic acid)-poly(uridylic acid) was used in quantitative microcomplement fixation assays to detect conformational variations among several double-helical polyribonucleotide analogs of poly(adenylic acid)-poly(uridylic acid) or poly(inosinic acid)-poly(cytidylic acid) that had been previously evaluated for their ability to induce interferon. Modification at the furanose 2'-position of one or both strands resulted in a dramatic decrease in serological reactivity. Most modifications of the bases caused smaller serological changes, and no base modification caused complete loss of reactivity. The reaction patterns support the conclusion that the structure of the furanose and the overall conformation of the helix are critical in the formation of antigenic determinants. The backbones of both strands appear to be involved in forming a single antigenic site, and base modifications may alter the steric relationship between the backbones. In addition, the same structural changes that substantially alter recognition by antibody also lead to large changes in the interferon-inducing ability of the nucleic acid.

Antigen-Antibody Reactions↗
PubMed1974

Interferon induction by synthetic polynucleotides: importance of purine N-7 and strandwise rearrangement.

The antiviral activity and interferon-inducing ability of single-, double-, and triple-stranded polynucleotides, modified at pyrimidine C-5 or purine N-7, were evaluated in primary rabbit kidney cells challenged with vesicular stomatitis virus. (1) There is a parallel increase in antiviral activity and the temperature at which double-stranded polynucleotides rearrange to inactive triple-stranded complexes. (2) When the purine N-7 of (A)(n) is replaced by CH, all resulting double-stranded complexes fail to provide antiviral protection or to induce interferon, even though such complexes meet all requirements previously recognized for interferon induction. (3) Competition experiments between inactive and active polynucleotides indicate that single-stranded polynucleotides apparently do not bind to the cellular receptor sites for interferon induction, whereas triple-stranded complexes and inactive double-stranded complexes bind to such receptor sites but, probably for conformational reasons, fail to trigger the necessary message for interferon induction.

Adenine Nucleotides↗
PubMedDate not supplied

The solid-phase synthesis of 2'-5'-linked oligoriboadenylates containing 8-bromoadenine.

To increase the accessibility of 8-bromo-2',5'-oligoadenylates, we developed a synthesis of 2'-5'-linked oligoriboadenylates containing varying numbers of 8-bromoadenosine residues based on the use of a CPG-LCA solid support and the phosphoramidite approach. Although N6-benzoyl protection was satisfactory for incorporation of nonmodified adenine residues into 2',5'-oligonucleotides, the effective incorporation of 8-bromoadenine into such 2',5'-linked oligomers required use of a non acyl protecting group. Amidine protection of the purine exocyclic amino function proved compatible with all aspects of the phophoramidite approach and with the hydroxyl protection groups employed.

Adenine↗
PubMedDate not supplied

2',5'-Oligoadenylate:antisense chimeras--synthesis and properties.

We have synthesized a novel bioconjugate which joins an antisense oligonucleotide to a unique and potent inhibitor of translation,pn5'A2'(p5'A2')mp5'A(2-5A). Two residues of 4-hydroxybutyl phosphate were employed as linkers to attach the 2',5'-oligoadenylate moiety through its 2'-terminus to the 5'-terminus of the chosen antisense sequence, (dT)20. The syntheses were carried on a solid support according to the phosphite triester method of DNA synthesis (Letsinger, R.L., Lunsford, W.B. (1976) J. Am. Chem. Soc. 98, 3655-3661; Beaucage, S.L., and Caruthers, M.H. (1981) Tetrahedron Lett. 22, 1859-1862). The generated 2-5A antisense chimeras retained both the ability of the 2-5A molecule to activate the 2-5A-dependent RNase as well as the ability of the oligo(dT) moiety to hybridize to the complementary poly(A). Moreover, the chimera, when annealed to its target nucleic acid sequence, was still effectively bound to the 2-5A-dependent nuclease. The methodology described represents a new approach to the selective modulation of mRNA expression.

Adenine Nucleotides↗
PubMedDate not supplied

Efficient functionalization of 2',5'-oligoadenylates with sulfur.

To derivatize the 2'-terminus of 2',5'-oligoadenylates with a thiol group, the reaction of periodate-oxidized nucleotide and 2',5'-oligonucleotide with aminothiols was explored. Two separate synthetic approaches were employed, both of which relied upon the use of S-protected thiols. In one approach, 5'AMP was oxidized with sodium periodate to dialdehyde, which was reacted with cystamine hydrochloride. Sodium cyanoborohydride reduction of the unisolated intermediate animal gave compound 4. The second approach involved reaction of S-(2-tetrahydropyranyl)cysteamine with the dialdehyde obtained by periodate oxidation of 5'AMP to yield, after reduction with Na(CN)BH3, the S-protected adduct 3. Intermediate 3 could be oxidized with aqueous iodine to give disulfide 4. Disulfide 4, obtained by either of the above routes, was reduced with dithiotreitol (DTT) to the thiol 5. This same reaction sequence was applied to 2-5A tetramer monophosphate, p5'A2'[p5'A2']2p5'A (6a), to give via 6b the 2'-terminal-modified derivative 6c. Aqueous iodine oxidation of 6c provided the disulfide 7, which reacted with DTT to give quantitative conversion to product, the free thiol 8. Both the disulfide 7 and the S-tetrahydropyranyl-protected derivative (6c) were bound effectively to the 2-5A-dependent RNase L of mouse L cells with IC50 values of 1 x 10(-9) M for 7 and 8 x 10(-10) M for 6c, not significantly different from the corresponding value for the parent unmodified 2-5A (6a) itself.

Adenine Nucleotides↗