Compounds that bind to human immunodeficiency virus rev response element
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11692010-B2
Publication Date
2023-07-04
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
Compounds that bind to human immunodeficiency virus (HIV) Rev response element (RRE) RNA are provided, including peptides or peptide mimetics that inhibit binding of Rev protein to the RRE RNA. In some embodiments, the compounds include two moieties, each binding to one of two Rev binding sites in the RRE, joined by a linkage of about 30-80 Å, which can be covalent or via a linker. These moieties include peptides (such as those comprising an arginine-rich motif) or small organic molecules, exemplified by aminoglycoside antibiotics such as neomycin B. The compounds may further include detectable labels or cargo moieties such as radioisotopes or toxins.
The problem addressed is the need for antiviral compounds that target viral RNAs, specifically the HIV RRE, since current anti-HIV drugs target viral proteins, not viral RNAs. Nuclear export of unspliced and singly spliced HIV RNA requires the specific interaction of Rev protein with the RRE RNA, a key step in HIV replication. Targeting this RRE represents a novel therapeutic approach to inhibit HIV infection by interfering with Rev binding.
Also disclosed are methods of inhibiting Rev binding to RRE by contacting the RRE with the compounds disclosed. Further methods include treating or inhibiting HIV infection by administering the compounds to subjects. Additional methods involve identifying cells containing HIV RRE using compounds linked to detectable labels and delivering cargo moieties to such cells to exert therapeutic effects. The disclosure includes pharmaceutical compositions and various routes and dosages for administration of these compounds.
Claims Coverage
The claims include one independent claim covering a compound with two linked peptides binding distinct Rev binding sites on HIV RRE RNA, and independent claims directed to compositions and methods using such compounds. The main inventive features relate to the compound structure, binding characteristics, linkage type, and applications in inhibition and detection.
Compound comprising two covalently linked peptides binding distinct Rev binding sites on HIV RRE RNA
The compound comprises two peptides, each binding a different Rev binding site on HIV RRE RNA; the peptides are covalently linked by a linkage about 30-80 Å in length. Each peptide is 18-23 amino acids long, 60-80% alpha-helical, and 40-60% arginine residues. The first peptide binds with affinity about 1 μM to 1 nM, and the second with affinity about 1 mM to 1 μM. The peptides are linked via a disulfide bond, thioester bond, or chemical crosslinker.
Chemical crosslinkers used for linking peptides
The linkage between peptides can be formed using chemical crosslinkers including succinimide, carbodiimide, maleimide, or hydrazide groups.
Peptide composition variations
One or both peptides can comprise L-amino acids, D-amino acids, or combinations thereof, and may be retro-inverso peptides.
Pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier
Compositions include the described compound formulated with a pharmaceutically acceptable carrier suitable for administration.
Methods of inhibiting Rev binding to HIV RRE RNA
Methods involve contacting the HIV RRE RNA with the compound to inhibit Rev binding.
Methods of treating or inhibiting HIV-1 infection in a subject
Treatment methods comprise administering an effective amount of the compound to a subject infected with HIV-1 to inhibit or treat the infection.
Compounds further linked to detectable labels
The compound can include one or more detectable labels linked to it for identification or imaging of HIV-infected cells.
Methods of identifying HIV-containing cells using the labeled compound
Cells are contacted with the compound linked to detectable labels; detection of the label identifies cells containing HIV.
Compounds further linked to cargo moieties
The compound can further include one or more cargo moieties such as toxins or agents that reduce cell viability linked to it.
Methods of delivering cargo moieties to HIV-containing cells
Delivery methods involve contacting HIV-containing cells with the compound linked to cargo moieties, thereby delivering the cargo specifically to infected cells.
The independent claims cover compounds with two linked peptides binding distinct Rev binding sites of HIV RRE RNA via a defined linkage, pharmaceutical compositions thereof, and methods of inhibiting Rev binding, treating HIV infection, detecting HIV-infected cells using labeled compounds, and delivering therapeutic cargo moieties to HIV-infected cells.
Stated Advantages
The compounds permit highly specific and high affinity inhibition of binding of Rev protein to HIV RRE RNA.
Targeting the viral RNA element RRE provides a novel mechanism distinct from all current anti-HIV drugs targeting viral proteins.
The unique compound design allows simultaneous binding to two Rev binding sites to achieve high specificity and affinity.
Compounds linked to detectable labels enable sensitive and specific detection of HIV-infected cells, even at early infection stages.
Compounds linked to therapeutic cargo moieties enable specific delivery of antiviral or cytotoxic agents to infected cells, potentially minimizing off-target effects.
Documented Applications
Treatment or inhibition of HIV-1 or HIV-2 infection by administering compounds that bind RRE and inhibit Rev binding.
Detection or identification of cells containing HIV by using compounds linked to detectable labels to bind HIV RRE RNA in those cells.
Delivery of therapeutic cargo moieties to cells containing HIV by linking cargo molecules to RRE-binding compounds for targeted therapy.
Use of compounds for inhibiting HIV viral replication by blocking Rev-RRE interaction, assessed by inhibition of viral protein synthesis and virus assembly.
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