Antiviral oligonucleotides having a conserved G4 core sequence

Abstract

Modified oligonucleotides having a conserved G4 sequence and a sufficient number of flanking nucleotides to significantly inhibit the activity of a virus or phospholipase A2 or to modulate the telomere length of a chromosome are provided. G4 quartet oligonucleotide structures are also provided. Methods of prophylaxis, diagnostics and therapeutics for viral-associated diseases and diseases associated with elevated levels of phospholipase A2 are also provided. Methods of modulating telomere length of a chromosome are also provided; modulation of telomere length is believed to play a role in the aging process of a cell and in control of malignant cell growth.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation of U.S. application Ser. No. 08 / 403,888 filed Jun. 12, 1995, which is the national phase of PCT Application Serial No. PCT / US93 / 09297 filed Sep. 29, 1993, which is a continuation-in-part of U.S. application Ser. No. 07 / 954,185 filed Sep. 29, 1992, now abandoned, each of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] This invention relates to the design and synthesis of oligonucleotides which can be used to inhibit the activity of viruses in vivo or in vitro and to treat viral-associated disease. These compounds can be used either prophylactically or therapeutically for diseases associated with viruses such as HIV, HSV, HCMV and influenza. Oligonucleotides capable of inhibiting phospholipase A2 enzyme activity are also provided which may be useful for the treatment of inflammatory disorders, as well as neurological conditions. Oligonucleotides designed for...

AI Technical Summary

Benefits of technology

[0033] It has been discovered that oligonucleotides containing the sequence GGGG (G4), denominated herein as a conserved G4 core sequence, have antiviral activity against a number of viruses including but not limited to HIV, HSV, HCMV, and influenza virus. A sequence containing 4 guanines (G's) or 2 stretches of 3 G's has been found to be effective for significant antiviral activity. It has also been discovered that oligonucleotides containing a conserve

Problems solved by technology

Although each of the above publications have reported some degree of success in inhibiting some function of the virus, a general therapeutic scheme to target HIV and other viruses has not been found.

IDU is a moderately effective topical antiviral agent when applied to HSV gingivostomatitis and ocular stromal keratitis; however, its use in controlled clinical studies of HSV encephalitis revealed a high toxicity associated with IDU treatment.

Reports of clinical efficacy are contradictory and a major disadvantage for practical use is the extremely poor solubility of Ara-A in water.

However there appear to be both the existence of drug-resistant viral mutants and negative results in double-blind studies of HSV-1 treatment with ACV.

ACV, like Ara-A, is poorly soluble in water (0.2%) and this physical characteristic limits the application forms for ACV.

The practical application of purine nucleoside analogs in an extended clinical situation suffers from their inherently efficient catabolism, which not only lowers the biological activity of the drug but also may result in the formation of toxic catabolites.

The efficacy of these compounds is diminished by their inherently poor solubility in aqueous solutions, rapid intracellular catabolism and high cellular toxicities.

Interferon, transfer factor, adenine arabinoside (Ara-A), acycloguanosine (Acyclovir, ACV) and certain combinations of these drugs have been ineffective in controlling CMV infection.

DHPG seems to be well tolerated by treated individuals, but the appearance of a reversible neutropenia, the emergence of resistant strains of CMV upon long-term administration, and the lack of efficacy against CMV pneumonitis limit the long term applications of this compound.

Such therapeutic approaches have failed for cytomegalovirus infections.

Therefore, there is an unmet need for effective compositions capable of inhibiting cytomegalovirus activity.

None, however, are effective against influenza type B. Moreover, they are generally of very limited use therapeutically and have not been widely used in treating the disease after the onset of symptoms.

To date, efforts at identifying non toxic and selective inhibitors of type II phospholipase A2 have met with little success.

While this research suggests that telomere length affects cell division, no effective method for control of the aging process or cancer has been discovered.

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