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Patent Issued for Small Molecule Inhibitors of Retroviral Assembly and Maturation




 



2012 NOV 12 (NewsRx) -- By a News Reporter-Staff News Editor at AIDS Weekly -- New York Blood Center, Inc. (New York, NY) has been issued patent number 8299093, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also New York Blood Center, Inc.).

The patent's inventors are Debnath, Asim Kumar (Fort Lee, NJ); Zhang, Hongtao (Oakland Gardens, NY); Curreli, Francesca (Bronx, NY).

This patent was filed on August 6, 2009 and was cleared and issued on October 30, 2012.

From the background information supplied by the inventors, news correspondents obtained the following quote: "Human immunodeficiency virus type 1 (HIV-1) is the etiological agent that causes acquired immunodeficiency syndrome (AIDS). According to the AIDS Epidemic Update (UNAIDS, December 2007) approximately 36 million people are living with HIV-1, particularly in Sub-Saharan Africa and South-East Asia. The introduction of highly active anti-retroviral therapy (HAART) has significantly contributed to the decreased morbidity and mortality among HIV-1 infected people; however, the patient's developed drug resistance severely limits treatment options available. The developed resistance and the failure of several therapies in recent clinical trials have reinforced the critical need to identify and utilize newer targets to develop new classes of anti-HIV-1 drugs that broaden the scope of treatment and reduce development of treatment resistant HIV-1 variants.

"HIV-1 infection involves the attachment of the virus to the host cell, reverse transcription of genetic material from viral RNA to DNA, integration of viral DNA with host DNA, replication of viral RNA from DNA, translation of viral RNA to create viral proteins, cleavage of viral proteins, assembly and packaging of viral proteins, and budding from the host cell.

"HIV-1 infection of a host immune cell first requires attachment of the virus to the cell membrane. On the surface membrane of all living cells are complex protein structures called 'receptors'. A receptor is often compared to a lock into which a specific key or 'ligand' will fit. Attachment of the virions to receptors on the host membrane enables fusion and the viral contents, including viral RNA, will empty into the cell's cytoplasm. Like other viruses that infect human cells, HIV-1 commandeers the host's machinery to make multiple copies of itself. Once the RNA has been copied and translated into proteins, the viral RNA and associated proteins are packaged and released from the host cell, taking with them a piece of the cell membrane.

"There are only nine genes in the HIV-1 genome. These genes have the code necessary to produce structural proteins, such as the viral core and enzymes like reverse transcriptase, integrase, and protease. One of the most important genes, the gag gene, encodes the Gag protein, the critical structure protein of HIV-1. In human cells infected by HIV-1, the viral Gag protein directs assembly of nascent viral particles at the plasma membrane, and thus, is a good target for disruption of retroviral assembly."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "The present disclosure describes pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof;

"##STR00001## wherein R.sub.1 and R.sub.2 are independently a moiety selected from the group consisting of (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted alkyl phenyl, substituted or unsubstituted aminophenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, and substituted or unsubstituted alkyl heterocycle; R.sub.3 is a moiety selected from the group consisting of H, and substituted or unsubstituted (C.sub.1-6)alkyl; Z is C.dbd.O, C.dbd.S or S(.dbd.O).dbd.O; and T, U, V, W and X are independently selected from CR.sub.4 or N, wherein R.sub.4 is a moiety selected from the group consisting of hydrogen, substituted or unsubstituted (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkoxy, hydroxyl alkyl, halogen, nitrile, amino, nitro, carboxyl, alkyl amino sulphonyl, substituted or unsubstituted aryl amino sulphonyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl. In some embodiments, the compound is selected from the group of compounds in Table 1. In other embodiments, the composition includes at least two compounds from Table 1.

"The present disclosure also describes pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt or ester thereof;

"##STR00002## wherein R.sub.1 is a moiety selected from the group consisting of hydrogen, substituted or unsubstituted (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkoxy, hydroxyl, hydroxy alkyl, halogen, nitrile, nitro, amino, sulphonyl, sulphonamido; R.sub.2 is a moiety selected from the group consisting of substituted or unsubstituted (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkoxy, carboxyl, alkyl amino sulphonyl, substituted or unsubstituted aryl amino sulphonyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted alkyl phenyl, substituted or unsubstituted aminophenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, and substituted or unsubstituted alkyl heterocycle; and A, V, W, X and Y are independently selected from CR.sub.3 or N, wherein R.sub.3 is a moiety selected from the group consisting of hydrogen, (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkyl, substituted or unsubstituted (C.sub.1-6)alkoxy, hydroxyl, hydroxy alkyl, halogen, nitrile, amino, nitro. In some embodiments, the compound is selected from the group of compounds in Table 2. In other embodiments, the composition includes at least two compounds selected from Tables 1 and 2.

"The present compositions may also include one or more pharmaceutically acceptable excipients and/or one or more additional therapeutic agents.

"The present systems and methods are also directed towards methods for disrupting HIV-1 assembly and replication. The methods may include administering to cells a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I or formula II, or pharmaceutically acceptable salts or esters thereof. The methods may utilize any of the compositions disclosed herein, including those disclosed in Tables 1 and 2.

"The methods may further include administering a compound of formula I and/or formula II with at least one additional therapeutic agent selected from the group consisting of reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, chemokine receptor (CXCR4, CCR5) inhibitors, interleukin-2, hydroxyurea, monoclonal antibodies, cytokines, and combinations thereof."

For the URL and additional information on this patent, see: Debnath, Asim Kumar; Zhang, Hongtao; Curreli, Francesca. Small Molecule Inhibitors of Retroviral Assembly and Maturation. U.S. Patent Number 8299093, filed August 6, 2009, and issued October 30, 2012. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=71&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=3533&f=G&l=50&co1=AND&d=PTXT&s1=20121030.PD.&OS=ISD/20121030&RS=ISD/20121030

Keywords for this news article include: Gases, Elements, HIV/AIDS, Hydrogen, Peptides, Virology, Viral DNA, Viral RNA, gag Genes, Amino Acids, RNA Viruses, Viral Genes, DNA Research, Retroviridae, HIV Infections, Viral Proteins, Genetic Phenomena, Genome Components, Genetic Structures, Vertebrate Viruses, Inorganic Chemicals, Primate Lentiviruses.

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Information in this article was accurate in November 12, 2012. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.