Zinc Finger Anti-HIV Licensing Opportunity
HIV Zinc Fingers
Article from August 1995 Antiviral Agents Bulletin
HIV Zinc Finger Therapeutics Screening and Development Opportunity
The National Cancer Inst. (NCI; Bethesda, MD) published an announcement in the Federal Register, August 10, seeking corporate partners to enter into a Collaborative Research and Development Agreement (CRADA) for screening and development of drugs that interfere with the CCHC zinc finger structures of HIV-1 and other retroviral nucleocapsid proteins. The nucleocapsid proteins of HIV-1 and other retroviruses contain regions known as CCHC zinc fingers that are highly conserved throughout nearly all retroviruses. The CCHC zinc fingers are sequences of 14 amino acids with four invariant residues, Cys(X)2Cys(X)4His(X)4Cys, that chelate zinc. HIV-1 has two zinc fingers separated by only seven amino acids and both of these are necessary for packaging genomic RNA and viral infectivity. Mutations in the CCHC zinc fingers render HIV-1 noninfectious and many compounds that disrupt the CCHC zinc fingers also inactivate HIV-1 virus.
NCI researchers report, ÒRetroviral CCHC zinc fingers are ideal targets for rational drug development because of their extreme conservation among Retroviridae and their essential roles in two steps of viral replication.Ó Since CCHC zinc fingers are highly conserved among nearly all retroviruses, assays based on interference with these structures are suitable for screening for drugs against HIV and other retroviruses including HTLV-I, HTLV-II, feline leukemia virus (FeLV), feline immunodeficiency virus (FIV) and equine infectious virus. Agents that interfere with zinc finger function include various electrophilic compounds and Òmany proprietary reagents identified through the NCI Drug Discovery Program.Ó These agents displace zinc and destroy the active configuration of the zinc fingers. Some active agents also react with nucleocapsid proteins. Candidate therapeutics are available that are nontoxic in vitro and are effective against field and laboratory isolates of HIV-1 (including monocytotropic strains and strains resistant to non-nucleoside inhibitors of reverse transcriptase), HIV-2 and SIV.
Relevant patent applications have been filed including U.S. 08/379,420 and 08/312,331, both entitled, ÒA Method for Identifying and Using Compounds that Inactivate HIV-1 and Other Retroviruses by Attacking Highly Conserved Zinc Fingers in the Viral Nucleocapsid Protein,Ó by Drs. L.E. Henderson, L.O. Arthur and W.G. Rice. The company that enters into the CRADA will have the option to exclusively license these and any other inventions resulting from the collaboration, and these inventions are also available for licensing without entering into a CRADA. Screening assays are provided for identifying compounds capable of disrupting retroviral CCHC zinc fingers and inactivating retroviruses, including HIV-1. Retroviral CCHC zinc fingers complex with two zinc ions, each with a formal charge of +2. Compounds that react with the CCHC zinc fingers and remove the zinc ions cause a change in the conformation and charge of the nucleocapsid protein, which can be detected as a change in its electrophoretic mobility using capillary zone electrophoresis (CZE) or other means. Purified CCHC zinc fingers may be reconstituted with radioactive zinc-65 and the release of zinc-65 caused by test compounds interacting with retroviral CCHC zinc fingers can be used to determine the reactivity of test compounds. Changes in the intrinsic fluorescence, fluorescence of artificial probes, or fluorescent zinc chelators can be used to monitor the loss of zinc from HIV-1 CCHC zinc fingers. Reverse phase high performance liquid chromatography (HPLC) can be used to separate CCHC zinc fingers that have been reacted with compounds resulting in covalent changes in these proteins. Nuclear magnetic resonance (NMR) can also be used to monitor the loss of zinc from retroviral CCHC zinc fingers. These assays do not utilize live virus and biosafety is not a concern. Several of these assays are adaptable for high throughput screening. Gel mobility shift assays can also be used to identify and study compounds able to penetrate intact virus and to induce conformational changes in the CCHC zinc fingers using HIV-1 or retroviruses that are not pathogenic for humans.
The CRADA partner will be expected to fully collaborate with NCI scientists in research, screening and therapeutics development and clinical testing; receive screening reagents and candidate drugs; be expected to support related research and Phase I-III clinical trials; manufacture candidate therapeutics; and obtain FDA approval. These and other patent applications may also be available for licensing without collaborating with NCI. For further information about CRADA opportunities contact:
Cindy K. Fuchs, J.D.
NCI-Frederick Cancer Res. and Dev. Center
P.O. Box B
Frederick, MD 21702-1201
Phone: 301-846-5465; FAX: 301-846-6820
For copies of patent applications (which may require signing a nondisclosure agreement) and inquiries about licensing contact:
Steven M. Ferguson
Acting Chief, Infectious Disease Branch
Office of Technology Transfer, NIH
6011 Executive Boulevard, Suite 325
Rockville, MD 20852-3804
Phone: 301-496-7735, ext. 266; FAX: 301-402-0220
PTO Issues New Clinical Utility Guidelines Ð The U.S. Patent and Trademark Office (PTO) published new guidelines for evaluation of clinical utility claims in the Federal Register, July 14, 1995 (p. 36263-5). PTOÕs intentions to liberalize and formally state its guidelines were discussed in the February Bulletin (p. 45). Claims for human efficacy of biopharmaceutical and other therapeutics will now be presumed valid based on appropriate in vitro and animal studies and expert (e.g., inventorsÕ) opinion. Previously, patent examiners had been rejecting many biopharmaceutical patents, citing a need to show efficacy in clinical trials. Biopharmaceutical and therapeutics patent applications will now essentially be treated the same as other patent applications, with claims presumed valid unless the patent examiners can find contradictory information.