# US 8,785,493 B2 · Treatment of retroviral reservoirs exploiting oxidative stress

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- Number: US 8,785,493 B2
- Document ID: US8785493B2
- Status: Granted
- Kind: B2
- Application number: 13/125,325
- Filed: 2009-10-29
- Published: 2011-12-15
- Granted: 2014-07-22
- Earliest claimed: 2008-10-29
- Assignees: Istituto Superiore di Sanita
- Applicants: Andrea Savarino; Antonello Mai; Anna Teresa Palamara; Enrico Garaci
- Inventors: Andrea Savarino; Antonello Mai; Anna Teresa Palamara; Enrico Garaci
- Web page: https://patentgrep.com/patent/US8785493B2

## CPC

- A61K 33/36: Arsenic; Compounds thereof
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/28: Compounds containing heavy metals
- A61K 31/295: Iron group metal compounds
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7024: Esters of saccharides
- A61K 33/04: Sulfur, selenium or tellurium; Compounds thereof
- A61K 33/26: Iron; Compounds thereof
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Activation of HIV-1 replication causes oxidative stress, which in turn potentiates HIV-1 replication. The common basis for the compounds of the present invention is: A) the capacity of reactivating HIV-1 from latency, and B) the ability to counteract the cellular machinery which activates in order to limit the effects of oxidative stress. In this way, oxidative stress can be potentiated and a “chain reaction” is sparked. This “chain reaction” induces a more efficient reactivation of HIV-1 from latency and, in some cases, induces selective killing of the infected cells. Actions A) and B) can either be carried out by one drug exerting both effects, or obtained by the combined use of distinct drugs. There are two main cellular machineries counteracting oxidative stress, i.e. the thioredoxin (Trx) thioredoxin reductase (TrxR) system and glutathione. Herein, we present drug strategies capable of exerting action B) by blocking either of the two machineries.

## Claims

### Claim 1

A method for selectively targeting a cell latently infected with human immunodeficiency virus (HIV), which method comprises contacting a cell with auranofin in an amount effective for inducing replication of the latent HIV, wherein the auranofin has an epigenetic effect on the latently infected cell.

### Claim 2 (depends on 1)

A method according to claim 1, in which the auranofin is administered in combination with at least one compound selected from the group consisting of: a histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA), butionine sulfoximine (BSO), iron nitriloacetate (FeNTA), and ferrous sulphate.

### Claim 3 (depends on 1)

A method according to claim 1, in which the cell is selected from the group consisting of an ACH-2 cell and a U1 cell.

### Claim 4 (depends on 1)

A method according to claim 1, additionally comprising administration of a conventional anti-retroviral therapy.

### Claim 5

A method for treating a retroviral infection in an individual, which method comprises administering, to the individual, auranofin in an amount effective for inducing replication of latent HIV, wherein the auranofin has an epigenetic effect.

### Claim 6 (depends on 5)

A method according to claim 5, wherein the auranofin is administered in combination with at least one compound selected from the group consisting of: a histone deacetylase inhibitor (HDCAI), suberoylanilide hydroxamic acid (SAHA), butionine sulfoximine (BSO), iron nitriloacetate (FeNTA) and ferrous sulphate.

### Claim 7 (depends on 5)

A method according to claim 5, additionally comprising administration of a conventional anti-retroviral therapy.

### Claim 8 (depends on 5)

A method according to claim 5, wherein the auranofin is administered in combination with suberoylanilide hydroxamic acid (SAHA).