Compounds that bind to human immunodeficiency virus rev response element

Patent metadata

Field	Value
Publication number	US-10464970-B2
Application number	US-201415031232-A
Country	US
Kind code	B2
Filing date	Oct 23, 2014
Priority date	Oct 23, 2013
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

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.

First claim

We claim:

1. A compound that binds to a human immunodeficiency virus (HIV) Rev response element (RRE) RNA, comprising two covalently linked peptides, wherein the compound comprises:
(a) two peptides each consisting of the amino acid sequence of SEQ ID NO: 3, covalently linked by a disulfide bond between cysteine residue 18 of each peptide;
(b) two peptides each consisting of the amino acid sequence of SEQ ID NO: 1, covalently linked by a cross linker between the carboxyl termini of the two peptides;
(c) two peptides each consisting of the amino acid sequence of SEQ ID NO: 2, covalently linked by a cross linker between the carboxyl termini of the two peptides;
(d) two peptides each consisting of the amino acid sequence of SEQ ID NO: 4, covalently linked by a disulfide bond between cysteine residue 15 of each peptide;
(e) two peptides each consisting of the amino acid sequence of SEQ ID NO: 5, covalently linked by a lysine-glutamic acid linkage between lysine residue 15 and glutamic acid residue 14;
(f) a first peptide consisting of the amino acid sequence of SEQ ID NO: 9 and a second peptide consisting of the amino acid sequence of SEQ ID NO: 19, wherein the carboxyl terminus of the first peptide is covalently linked to the amino terminus of the second peptide by a linker;
(g) a first peptide consisting of the amino acid sequence of SEQ ID NO: 9 and a second peptide consisting of the amino acid sequence of SEQ ID NO: 20, wherein the carboxyl terminus of the first peptide is covalently linked to the amino terminus of the second peptide by a linker; or
(h) two peptides each consisting of the amino acid sequence of SEQ ID NO: 7, covalently linked by a disulfide bond between cysteine residue 16 of each peptide.

2. The compound of claim 1 , wherein one or both of the peptides comprise at least one L-amino acid or at least one D-amino acid, one or both of the peptides are a retro-inverso peptide, or a combination thereof.

3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

4. A method of inhibiting binding of Rev to an HIV Rev response element (RRE) RNA, comprising, contacting the RRE with the compound of claim 1 .

5. The method of claim 4 , wherein contacting the RRE RNA with the compound or composition comprises contacting a cell comprising RRE RNA with the compound or composition.

6. The method of claim 5 , wherein contacting the cell comprising RRE RNA with the compound or composition comprises administering the compound or composition to a subject infected with or suspected to be infected with HIV.

7. A method of treating a subject infected with HIV-1, comprising administering to the subject an effective amount of the compound of claim 1 .

8. The compound of claim 1 , further comprising one or more detectable labels linked to the compound.

9. The compound of claim 8 , wherein the one or more detectable labels comprise a radiolabel, a fluorescent molecule, a magnetic or paramagnetic particle, a nanoparticle, an enzyme, a hapten, or a combination of two or more thereof.

10. A method of identifying a cell containing HIV, comprising:
contacting one or more cells with the compound of claim 8 ;
detecting presence of the detectable label; and
identifying a cell having the presence of the detectable label as a cell containing HIV.

11. The method of claim 10 , wherein the contacting the one or more cells with the compound comprises administering the compound to a subject infected with or suspected to be infected with HIV.

12. The compound of claim 1 , further comprising one or more cargo moieties.

13. The compound of claim 12 , wherein the one or more cargo moieties comprise a radioisotope, a free radical generator, a crosslinking agent, or a cytotoxin.

14. The compound of claim 13 , wherein the cytotoxin comprises a bacterial toxin, a pore-forming toxin, a pro-apoptotic compound, or an inhibitor of an anti-apoptotic compound or the free radical generator comprises a hydroxyl radical generator.

15. A method of delivering a cargo moiety to a cell containing HIV, comprising contacting a cell containing HIV with the compound of claim 12 , thereby delivering the cargo moiety to the cell containing HIV.

16. The method of claim 15 , wherein the contacting the cell containing HIV with the compound comprises administering the compound to a subject infected with or suspected to be infected with HIV.

17. The method of claim 7 , further comprising administering one or more additional HIV treatment agents to the subject infected with HIV.

18. The compound of claim 1 , wherein the cross linker of part (b) or (c) or the linker of part (f) or (g) comprises succinic acid or succinate.

Assignees

• Us Health

Inventors

• Wang yun-xing
• Yu Ping

Classifications

• C12Q1/703

  Viruses associated with AIDS · CPC title

• C12N2740/16011

  Human Immunodeficiency Virus, HIV · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K49/14

  Peptides, e.g. proteins · CPC title