A Novel Approach to HIV Treatment Through nSMase Inhibition

Introduction

The global fight against human immunodeficiency virus (HIV) remains one of the most significant public health challenges. While current antiretroviral therapies (ART) have made tremendous progress in managing the disease and extending patient lifespans, there is still no cure. Moreover, resistance to traditional therapies and long-term side effects continue to be major concerns. Our patented approach targeting the inhibition of nSMase offers a new pathway to potentially disrupt HIV replication, providing a promising alternative or complement to existing treatment regimens.

The Need for Innovative HIV Treatments

Although antiretroviral therapies have successfully controlled HIV for millions of people worldwide, these drugs are not without limitations. They often require lifelong adherence, and any interruption in treatment can lead to viral rebound. Additionally, patients may develop resistance to their ART regimen, leaving fewer treatment options. Managing long-term toxicity and side effects also poses significant challenges, as does the virus’s ability to integrate into host DNA and remain dormant. These obstacles highlight the need for new therapeutic strategies that go beyond the current standard of care.

Disrupting HIV Replication Through nSMase Inhibition

Our technology targets nSMase, a critical enzyme involved in the viral replication process of HIV. By inhibiting nSMase activity, this therapeutic approach aims to prevent the virus from spreading within the body. This mechanism offers a novel route to attack the virus, potentially reducing the viral load while minimizing some of the challenges associated with traditional ART drugs.

One of the key advantages of this approach is its potential to work synergistically with existing HIV therapies, enhancing the overall effectiveness of treatment. Furthermore, nSMase inhibition may reduce the risk of drug resistance developing, offering patients a more robust and long-lasting solution. This patent also opens the door to developing therapies that could mitigate some of the chronic inflammatory conditions often associated with HIV, improving overall patient health and quality of life.

What Makes This Approach Stand Out

Unique Mechanism of Action: Inhibiting nSMase directly targets the viral replication process, offering an entirely new way to manage HIV infections.
Potential for Synergy: This approach can complement current ART treatments, enhancing efficacy and offering a multi-faceted attack against the virus.
Reduced Drug Resistance: Targeting a different aspect of the viral lifecycle reduces the likelihood of resistance, a critical advantage in long-term treatment plans.
Better Patient Outcomes: This technology has the potential to not only control viral loads more effectively but also improve overall health by reducing inflammation associated with HIV.

An Essential Opportunity for the Future of HIV Treatment

Licensing this nSMase inhibition technology offers a unique opportunity to bring a new class of HIV therapies to market. With the global HIV epidemic still requiring innovative solutions, this approach provides hope for both improving current treatments and addressing unmet medical needs in the fight against the virus.

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Abstract
Claims

Methods for treating a Human Immunodeficiency Virus (HIV) infection comprising administering to a subject in need of treatment thereof an effective amount of a small molecule nSMase2 inhibitor.

That which is claimed:

1. A method for treating a Human Immunodeficiency Virus (HIV) infection, the method comprising administering to a subject in need of treatment thereof an effective amount of an nSMase2 inhibitor of formula (I), wherein the compound of formula (I) is:

wherein:

R₃is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted thioalkyl, and substituted or unsubstituted aryl;

R₄is selected from the group consisting of H, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl;

R₅is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and a substituted or unsubstituted multicyclic aryl or multicyclic heteroaryl ring;

R₆is selected from the group consisting of H or substituted or unsubstituted C_1-6alkyl;

R₇is selected from the group consisting of —C(═O)—(CR_yR_z)_m—R₈, —C(═O)—(CR_yR_z)_m—O—R₈, —C(═O)—O—(CR_yR_z)_m—R₈, and —S(═O)₂—R₉, wherein each m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, R_yand R_zare each independently H, alkoxyl, or halogen, R₈and R₉are each independently selected from the group consisting of substituted or unsubstituted alkyl, —CF₃, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloheteroaryl, substituted or unsubstituted multicyclic aryl or heteroaryl ring, and NR₁₀R₁₁, wherein R₁₀and R₁₁are each independently selected from the group consisting of H, substituted or unsubstituted C_1-6alkyl, and substituted or unsubstituted aryl; and

pharmaceutically acceptable salts thereof.

2. The method of claim 1, wherein the compound of formula (I) is:

wherein:

p is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5;

each R₁₂is independently selected from the group consisting of substituted or unsubstituted alkyl, hydroxyl, alkoxyl, halogen, cyano, amino, —CF₃, —O—CF₃, substituted or unsubstituted cycloheteroaklyl, —NR₁₃(C═O)R₁₄, —S(═O)₂—R₁₅, —S(═O)₂—NR₁₅R₁₆, —SR₁₆, —C(═O)—R₁₇, —C(═O)—O—R₁₈, and —C(═O)—NR₁₉R₂₀, wherein R₁₃is selected from the group consisting of H or substituted or unsubstituted C_1-6alkyl, R₁₄is substituted or unsubstituted C_1-6alkyl or —O—R₂₁, and R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁are each independently H or substituted or unsubstituted C_1-6alkyl.

3. The method of claim 2, wherein R₆is H and R₇is —C(═O)—(CR_yR_z)_m—R₈, wherein m is 0 and R₈is C_1-6alkyl.

4. The method of claim 3, wherein the compound of formula (I) is selected from the group consisting of:

5. The method of claim 2, wherein R₆is H and R₇is selected from the group consisting of —C(═O)—(CR_yR_z)_m—R₈, —C(═O)—(CR_yR_z)_m—O—R₈, —C(═O)—O—(CR_yR_z)_m—R₈, wherein each m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, R_yand R_zare each independently H, alkoxyl, or halogen, R₈is selected from the group consisting of substituted or unsubstituted alkyl, —CF₃, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloheteroaryl, substituted or unsubstituted multicyclic aryl or heteroaryl ring, and NR₁₀R₁₁, wherein R₁₀and R₁₁are each independently selected from the group consisting of H, substituted or unsubstituted C_1-6alkyl, and substituted or unsubstituted aryl.

6. The method of claim 5, wherein the compound of formula (I) is selected from the group consisting of:

7. The method of claim 2, wherein R₆is H and R₇is —S(═O)₂—R₉.

8. The method of claim 5, wherein the compound of formula (I) is selected from the group consisting of:

9. The method of claim 1, wherein R₅is a substituted or unsubstituted multicyclic aryl or multicyclic heteroaryl ring.

10. The method of claim 9, wherein the compound of formula (I) is selected from the group consisting of:

11. The method of claim 1, wherein R₅is a substituted or unsubstituted heteroaryl.

12. The method of claim 11, wherein the compound of formula (I) is selected from the group consisting of:

13. The method of claim 1, wherein the administration of an effective amount of a compound of formula (I) to the subject has one or more effects selected from the group consisting of:

(a) decreases or inhibits the (nSMase2) activity in the subject;

(b) interferes with the HIV life cycle;

(d) prevents HIV viral assembly;

(e) prevents HIV budding; and

(f) prevents viral replication by blocking HIV budding from HIV-infected cells in the subject.

14. The method of claim 6, wherein the compound of formula (I) is:

Title

Inhibition of nSMase for the treatment of human immunodeficiency virus infection

Inventor(s)

Norman Haughey, Barbara Slusher, Camilo Rojas

Assignee(s)

Johns Hopkins University

Patent #

11759466

Patent Date

September 19, 2023