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Government-Owned Inventions; Availability for Licensing: Conformationally Locked Nucleoside Analogs as Antiherpetic Agents

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National Institutes of Health, Public Health Service, DHHS.




The inventions listed below are owned by agencies of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.


Licensing information and copies of the U.S. patent applications listed below may be obtained by contacting Peter A. Soukas, J.D., at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7056 ext. 268; fax: 301/402-0220; e-mail: A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

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These inventions relate to therapeutics for Herpes Simplex Virus (HSV), a major public health threat. Results of a recent, nationally representative study show that genital herpes infection, caused by HSV-2, is common in the United States. Nationwide, 45 million people ages 12 and older, or one out of five of the total adolescent and adult population, is infected with HSV-2. Once infected with HSV, people remain infected for life. The inventors' research has shown that these compounds are significantly more potent than current therapeutics for HSV. Development of these inventions would provide a significant benefit to the public health in the form of potentially lower cost therapeutics based on the potency of the compounds.

Conformationally Locked Nucleoside Analogues

Victor E. Marquez, Juan B. Rodriguez, Marc C. Nicklaus, Joseph J. Barchi, Jr., Maqbool A. Siddiqui (NCI)

U.S. Patent 5,629,454 issued 13 May 1997; U.S. Patent 5,869,666 issued 9 Feb 1999; PCT/US94/10794 (issued as European Patent Number 0720604 and Australian Patent Number 677441)


Conformationally Locked Nucleoside Analogs as Antiherpetic Agents

Victor E. Marquez, Juan B. Rodriguez, Marc C. Nicklaus, Joseph J. Barchi, Jr., Maqbool A. Siddiqui (NCI)

U.S. Patent 5,840,728 issued 23 Nov 1998

The compounds of the present invention represent the first examples of carbocyclic dideoxynucleosides that in solution exist locked in a defined N-geometry (C3′-endo) conformation typical of conventional nucleosides. These analogues exhibit increased stability due to the substitution of carbon for oxygen in the ribose ring. The invention includes 4′-6′-cyclopropane fused carbocyclic dideoxynucleosides, 2′-deoxynucleosides and ribonucleosides as well as oligonucleotides derived from these analogues; the preferred embodiment of the invention is carbocyclic-4′-6′-cyclopropane-fused analogues of dideoxypurines, dideoxypyrimidines, deoxypurines, deoxypyrimidines, purine ribonucleosides and pyrimidine ribonucleosides. In addition, oligonucleotides derived from one or more of the nucleosides in combination with the naturally occurring nucleosides are within the scope of the present invention.

The second invention discloses a method for the treatment of herpes virus infections by the administration of cyclopropanated carbocyclic 2′-deoxynucleosides to an affected individual. This invention is a method of administration of the compounds described above. The compounds of this invention are particularly efficacious against herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr Virus (EBV) and human cytomegalovirus (CMV), although the nucleoside analogues of the invention may be used to treat any condition caused by a herpes virus. Specifically, the N-methanocarba-T (Thymidine) analogue has been shown to exhibit strong activity against HSV-1 and HSV-2, and moderate to strong activity against EBV. Significantly, the anti-HSV activity of the Thymidine analogue is stronger than that of Acyclovir (shown in a plaque reduction assay), a widely used anti-HSV therapeutic. Furthermore, the Thymidine analogue is also non-toxic against stationary cells and is potent against rapidly dividing cells. Dosage amounts for the compounds are similar to those of Acyclovir.

Descriptions of these inventions may be found in Rodriguez et al., J. Medicinal Chemistry 37:3389-3399 (1994) and Marquez et al., J. Medicinal Chemistry 39:3739-3747 (1996).

5-Substituted Derivatives of Conformationally Locked Nucleoside Analogues

Victor Marquez, Pamela Russ (NCI)

DHHS Reference No. E-249-00/0, U.S. S/N 60/220,934 filed 26 Jul 2000

This invention relates to 5-substituted derivatives of conformationally locked nucleoside analogues and methods of using these derivatives as antiviral and anticancer agents. The compounds contemplated by the invention are nucleoside analogues where the 5-substituent is a halogen, alkyl, alkene, halovinyl or alkyne group, and the nucleotide base is cytosine or uracil. The analogues are particularly effective in treating viral infections, specifically infections of DNA viruses such as Herpes simplex virus (HSV), Varicella zoster virus (VSV), Epstein Barr virus (EBV), and Cytomegalovirus (CMV) as well as members of the Poxviridae family. The inventors have Start Printed Page 33106demonstrated in plaque reduction assays that 5-substituted uracils (bromo, iodo, and bromovinyl) attached to a bicyclo[3.1.0]hexane template are thirty times more potent than acyclovir against HSV-1 and HSV-2.

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Dated: June 11, 2001.

Jack Spiegel,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.

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[FR Doc. 01-15459 Filed 6-19-01; 8:45 am]