Effect of the extent of thiolation and introduction of phosphorothioate internucleotide linkages on the anti-HIV activity of Suligovir [(s4dU)35].

Suligovir is a 35-mer homo-oligonucleotide, containing exclusively 4-thio deoxyuridylate, proved to be a potent inhibitor of HIV entry. In this paper, we described the effect of extent of thiolation and the introduction of nuclease-resistant phosphorothioate linkages on the anti-HIV activity of Suligovir. We found that the decreased thiolated nucleotide content decreases the anti-HIV potency of the compound and the introduction of phosphorothioate linkages does not improve its antiviral activity.

Potent inhibition of HIV-1 entry by (s4dU)35.

We have previously reported the potent in vitro HIV-1 anti-reverse transcriptase activity of a 35-mer of 4-thio-deoxyuridylate [(s(4)dU)(35)]. In efforts to define its activity in a more physiological system, studies were carried out to determine the stage of viral infection that this compound mediates its anti-viral effect. Results of the studies reported herein show that (s(4)dU)(35) is nontoxic and is capable of inhibiting both single and multi-drug resistant HIV strains (IC(50): 0.8-25.4 microg/ml) in vitro. Besides its previously reported anti-RT activity, (s(4)dU)(35) mediated its antiviral action by preventing virus attachment (IC(50): 0.002-0.003 microg/ml), and was stable in vitro and slowly degraded by DNAses. Competition studies and fluorescence resonance energy transfer (FRET) experiments indicated that (s(4)dU)(35) preferentially binds to CD4 receptors, but not to CD48. Confocal laser scanning microscopy (CLSM) studies showed that (s(4)dU)(35) did not penetrate into the cells and colocalized with cell surface thioredoxin. Our studies identify (s(4)dU)(35) as a potential novel HIV entry inhibitor that may have utility as either a systemic antiretroviral or as a preventing agent for HIV transmission.

Effect of increasing thiolation of the polycytidylic acid strand of poly I:poly C on the alpha, beta and gamma interferon-inducing properties, antiviral and antiproliferative activities.

Double-stranded RNAs induce interferons and cause the development of antiviral and antiproliferative activities. Antiviral activity is related to the production of interferons and other proteins that stimulate various immunologic activities, which appear to contribute to their overall antiproliferative activity. The most active double-stranded RNA, polyI:polyC, was shown to be too toxic for therapeutic use. We conducted selective thiolation of the polyC strand at the five position of the cytosine bases, generating a partially thiolated polyC (MPC) which after annealing with a complimentary unmodified polyI, gave the thiolated double-stranded RNA, pI:MPC. We have explored antiviral and antiproliferative activities at various levels of thiolation and found that optimal responses can be obtained at 7.4% level of thiolation. This compound deserves further study of antiviral and antiproliferative responses in vivo, and eventually clinical exploration. Earlier studies have shown that this and related compounds are active against HIV-1, in human cells, and against DNA polymerases of DNA and RNA tumor viruses.

Field evaluation of capsaicin as a rodent aversion agent for poultry feed.

Developing additional techniques for reducing animal feed contamination by rodents and controlling rodent populations is critical to efforts aimed at reducing the occurrence of Salmonella spp infection on poultry farms. Capsaicin, a compound found in chili peppers of the genus Capsicum, produces a burning sensation in the mouth of mammals and is used effectively as an animal deterrent for some pest species. Applied to poultry feed, capsaicin may be effective as an aversive agent to deter rodent feeding and enhance acceptability of rodenticide baits. We tested capsaicin-treated poultry diets (2000 and 3000 Scoville Heat Units, SHU) in no-choice feeding trials at four active New York farms in the winter of 1997-1998. At all farms, consumption of the 2000 SHU diet by rodents (Norway rats, Rattus norvegicus (Berk), and house mice, Mus musculus L) was significantly less than consumption of a control diet. Consumption of the 3000 SHU diet by rodents was significantly less than consumption of a control diet at three of the four farms. Overall, consumption of treated diets was 58-97% and 55-98% less than consumption of the control diet, for the 2000 and 3000 SHU diets, respectively. These reductions appeared to be related closely to the availability of alternative feed sources at these farms. Two-choice feeding trials involving a rodenticide bait (0.05 g kg(-1) brodifacoum) and the 3000 SHU diet demonstrated that Norway rats preferred the rodenticide to the capsaicin-treated poultry feed. Overall, rodenticide bait acceptance was high (95.6%) when offered simultaneously with capsaicin-treated poultry feed. Although poultry managers must utilize several techniques to manage rodent pests, the use of capsaicin-treated diets to reduce feed losses and increase rodenticide bait acceptance appears promising. Use of capsaicin-treated feed on poultry farms may substantially reduce feed contamination by rodents and ultimately the incidence of Salmonella infection in poultry.