Compounds that bind to human immunodeficiency virus rev response element
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10464970-B2
Publication Date
2019-11-05
Expiration Date
2034-10-23
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Abstract
Compounds (such as peptides or peptide mimetics) that bind to HIV RRE RNA are provided. In some examples, the compounds inhibit (for example, decrease) binding of Rev to the RRE RNA. In some embodiments, the compounds include two moieties, each of which bind to one of the Rev binding sites in the RRE. In some examples, the moieties include peptides or small molecules. In some examples, the peptides include an arginine-rich motif. The RRE binding compounds may be further linked to a detectable label or cargo moiety. Also provided are methods of treating or inhibiting HIV including administering one or more of the RRE binding compounds to a subject.
Core Innovation
This patent discloses compounds that bind to the human immunodeficiency virus (HIV) Rev response element (RRE) RNA, particularly compounds that inhibit or decrease binding of the HIV Rev protein to the RRE RNA. The compounds may include two moieties, each binding to one of the two Rev binding sites in the RRE, linked together by a linkage of about 30-80 Å, which can be covalently linked either directly or via a linker. The moieties can be peptides, peptide mimetics, small organic molecules such as aminoglycoside antibiotics, or combinations thereof. Exemplary peptides include those containing an arginine-rich motif and variants such as retro-inverso peptides, with sequences represented by SEQ ID NOs: 1-20. The disclosed compounds can also be further linked to a detectable label or cargo moiety for diagnostic or therapeutic purposes.
The problem solved by this invention arises from the essential role of the Rev-RRE interaction in HIV's viral life cycle, specifically in the nuclear export of unspliced and singly spliced HIV RNA. Existing anti-HIV drugs primarily target viral proteins and not viral RNAs such as the RRE. The RRE's unique structure and topological arrangement, including two distinct Rev binding sites separated by about 55 Å, were previously not fully characterized, which hindered the development of compounds specifically targeting the Rev-RRE interaction. The invention addresses the need for new compounds that can bind to the RRE RNA, inhibit Rev binding, and thereby disrupt HIV replication.
By elucidating the three-dimensional structure of the HIV RRE RNA and identifying the spatial arrangement and distance between the two critical Rev binding sites, the patent enables the design of high-affinity, high-specificity compounds that simultaneously engage both sites. Such compounds inhibit the formation of the Rev-RRE complex necessary for viral RNA export. Additionally, linking the compounds to detectable labels allows sensitive identification of HIV-infected cells, and linking to cargo moieties provides targeted therapeutic delivery to HIV-containing cells, offering novel methods for treating HIV infection.
Claims Coverage
The patent includes one independent claim directed to compounds that bind to HIV RRE RNA, comprising two covalently linked peptides with specified sequences and linkages, as well as independent method claims involving inhibition of Rev binding, treatment of HIV, identification of HIV-containing cells, and delivery of cargo moieties.
Compounds with two covalently linked peptides specifically binding HIV RRE RNA
Compounds comprise two peptides each consisting of specific amino acid sequences (e.g., SEQ ID NO: 1, 2, 3, 4, 5, 7, 9, 19, 20) covalently linked via disulfide bonds, cross linkers, lysine-glutamic acid linkages, or a linker between termini, designed to bind to HIV RRE RNA.
Peptides containing L-amino acids, D-amino acids, or retro-inverso peptides
The peptides in the compound may comprise L- or D-amino acids or be retro-inverso peptides to potentially enhance stability or binding characteristics.
Pharmaceutical compositions comprising the disclosed compounds
Formulations that include the compounds and pharmaceutically acceptable carriers suitable for therapeutic administration.
Methods of inhibiting binding of Rev to HIV RRE RNA
Methods of inhibiting binding include contacting the RRE RNA with the compound in vitro or in cells or administering the compound to subjects infected with or suspected of having HIV.
Methods of treating subjects infected with HIV
Treatment methods involve administering an effective amount of the disclosed compounds to a subject infected with HIV-1 to inhibit viral replication and infection.
Compounds linked to detectable labels for identification of HIV-containing cells
Compounds further comprising one or more detectable labels (radioisotopes, fluorescent dyes, magnetic labels, nanoparticles, enzymes, haptens) allowing identification of HIV-containing cells via detection of the label after contacting cells with the compound.
Methods for identifying HIV-containing cells using labeled compounds
Methods include contacting cells with labeled compounds, detecting the label, and identifying cells containing HIV based on label presence; contacting can be in vitro or in vivo.
Compounds linked to therapeutic cargo moieties
Compounds further comprising cargo moieties such as radioisotopes, free radical generators (e.g., hydroxyl radical generator), nucleic acid crosslinking agents, or cytotoxins (e.g., bacterial toxins, pore-forming toxins, pro-apoptotic compounds, inhibitors of anti-apoptotic compounds) for targeted delivery to HIV-containing cells.
Methods of delivering cargo moieties to HIV-containing cells
Delivering cargo moieties by contacting HIV-containing cells with the compound linked to cargo, including administration to subjects infected with or suspected to have HIV.
Combination therapy with additional HIV treatment agents
Administration of the compounds disclosed along with one or more additional HIV therapeutics such as reverse transcriptase inhibitors, protease inhibitors, or integrase inhibitors.
The claims collectively cover the design and use of compounds comprising two covalently linked peptides targeting the two defined Rev binding sites in the HIV RRE RNA, including their pharmaceutical formulations, methods of inhibiting Rev binding, HIV treatment, detection of HIV-infected cells by labeled compounds, delivery of therapeutic cargo moieties, and use in combination therapies.
Stated Advantages
Highly specific and high-affinity binding to the HIV RRE RNA by targeting both Rev binding sites concurrently.
Simultaneous disruption of the Rev-RRE interaction and potential destruction of the viral RNA, providing a specific method to treat or inhibit HIV infection.
Provision of compounds that permit detection of HIV infection with extremely high sensitivity and specificity, even at early stages of infection.
Potential minimization of toxic effects on non-infected cells by targeted delivery of cargo moieties to HIV-infected cells using RRE-binding compounds.
Documented Applications
Treatment or inhibition of HIV-1 and HIV-2 infections by administering compounds that bind HIV RRE and inhibit Rev binding.
Methods for identifying and diagnosing HIV infection by detecting HIV-containing cells using compounds linked to detectable labels.
Targeted delivery of therapeutic cargo moieties (radioisotopes, toxins, RNA cleavage agents) specifically to HIV-infected cells.
Use in pharmaceutical compositions for treating HIV or AIDS, including combination therapies with known anti-retroviral agents.
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