Polycytidylic acid

Lactide/glycoUde polymers have been investigated for delivery of several other macromolecules. Synthetic double-stranded RNA, poly-isosinic acid/polycytidylic acid, a potent inducer of interferon, was formulated in a 53 47 copolymer of DL-lactide-co-glycoUde. The microspheres were evaluated in mice challenged with Right Valley fever virus. More than 16 days protection was afforded versus only 3 days for controls (137). 

Interferon is a low molecular weight protein, produced by vims-infected cells, that itself induces the formation of a second protein inhibiting the transcriphon of viral mRNA. Interferon is produced by the host cell in response to the vims particle, the viral nucleic and non-viral agents, including synthetic polynucleides such as polyinosinic acid polycytidylic acid (poly I C). There are two types of interferon. 

C. Oligo- and Poly-nucleotides.—The stepwise enzymatic synthesis of internucleotide bonds has been reviewed. A number of polynucleotides containing modified bases have been synthesised " in the past year from nucleoside triphosphates with the aid of a polymerase enzyme, and the enzymatic synthesis of oligodeoxyribonucleotides using terminal deoxynucleotidyl transferase has been studied. Primer-independent polynucleotide phosphorylase from Micrococcus luteus has been attached to cellulose after the latter has been activated with cyanogen bromide. The preparation of insolubilized enzyme has enabled large quantities of synthetic polynucleotides to be made. The soluble enzyme has been used to prepare various modified polycytidylic acids. ... 

Polynucleotides. Polynucleotides are potent interferon inducers. A mismatched, double-stranded synthetic polyribonucleotide ampligen and the double-stranded acids, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acids have been widely studied for cancer therapy(ii). Although these materials elicit excellent activity with murine rodents, therapeutic effects are dramatically decreased within primates. 

Early infrared (IR) spectroscopy studies were inconclusive some37 38 were considered to indicate that cytosine exists in the amine-lactim form (1) in the solid state, others39-41 that it exists in the amine-lactam form (2 or 3). More recent studies42-50 (for reviews, see refs. 51, 52) on cytidine, 5-halodeoxycytidines, sodium cytidylate, and polycytidylic acid in neutral H20 or D20 solution advocate, however, the structure 2 for the cytosine residue. 

Figure 2. Fiber diffraction from the sodium salt of polycytidylic acid recorded on a flat film perpendicular to the indicident x-ray beam. The fiber was at a 75° angle to the beam to permit the meridional diffraction on layer line 6 to be recorded. The lattice is trigonal with a = b — 2.32 nm c = 1.86 nm. The molecules are...

Lysine-rich proteinoids preferentially interact to form microparticles with polycytidylic acid and polyuridylic acid. On the other hand arginine-rich proteinoids interacts much more readily with polyguanylic acid and polyinosinic acid to form such particles under the same condition57>. Lysine-rich proteinoids had most often shown a preferential precipitation with polyuridylic acid in the experiments for interaction between polynucleotides and the proteinoids in the presence of Mg2+ 56). 

Partially thiolated polycytidylic acid (MPC) and various thiolated DNA and RNA isolates inhibited the DNA polymerases of tumor viruses and showed some significant selectivities129,130) (see the article by Dr. Chandra in this volume for more information). Studies of the effects of two, partially thiolated polyribonucleotides on the various types of DNA polymerase activities... 

Mercapto- 5-SH)-polycy tidy lie acid has been shown by Bardos et al.55 to block the DNA-directed RNA synthesis at 1/2 to 1/50 of the concentration of the unmodified DNA template used in the reaction. This mercapto derivative of polycytidylic acid (MPC) has been prepared by partial thiolation of polycytidylic acid (PC) according to the general procedure of Bardos et al.56> 57> the thiolated compound was gel-filtered through a Sephadex column and subsequently, through an Agarose-1.5 m (Bio-Gel A-l.5 m, exclusion limit 1,5000.000 mol. wt., Bio-Rad Labs.) column, then lyophilized and redissolved in 0.1 M Tris-buffer58). This compound (conversion of 9.5% of the cytidylate units to 5-mercaptocytidylate) was studied in the DNA-polymerase system of oncorna viruses. 

Fig. 23. Effects of thiolated polycytidylic acid (MPC) and unmodified polycytidylic acid (PC) on the DNA polymerase activities from MSV (Moloney) in the presence of poly rA-(dT)j4 ( ------ ) and poly (dA-dT) (O------O) as templates...

Fig. 23 shows the effects of 5-mercapto-(9.5%)-polycytidylic acid (MPC) and modified polycytidylic acid (PC), respectively, on the incorporation of 3H—TMP into DNA by the DNA-polymerses of the MSV-M, in the presence of either poly.(dA-dT) or poly rA (dT)i4 as the template. The results obtained with the same pair of modified and unmodified polycytidylic acid samples in... 

Giri SN, Hyde DM. 1988. Ameliorating effect of an interferon inducer poly-inosinic-polycytidylic acid on bleomycin-induced lung fibrosis in hamsters morphologic and biochemical evidence. Am. J. Pathol. 133 525-36... 

Dennis JW (1986) Effects of swainsonine and polyinosinic polycytidylic acid on murine tumor cell growth and metastasis. Cancer Res 46 5131-5136... 

The NMR results show that, in the case of 3 and 5 nucleotides, the binding of metal, or at least copper, does occur at Nj for adenine and guanine and at Ni for cytosine very little binding of copper occurs in thymine, the methyl derivative of uracil. NMR studies have also shown us that in the polymeric nucleic acids binding occurs generally in the same position as in these monomers. For example, in polyadenylic acid, the binding is also at Nj, and in polycytidylic acid it is at Ni. 

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