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US 9,956,260 B1Granted
Treatment of HIV-1 infection and AIDS
AssigneeThe J. David Gladstone Institutes
InventorsWarner C. Greene, Gilad Doitsh, Orlando Zepeda, Nicole Galloway
Life of this patent
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Abstract
Provided herein are compositions and methods for the treatment of a patient having an HIV-1 infection and/or AIDS. More specifically this invention provides treatment of an HIV-1 infection and/or AIDS using small molecule compounds, such as inhibitors for the activation and/or activity of caspase-1. Inhibitors for the activation and/or activity of caspase-1 also prevent the cell death of CD4 T-cells in a population of CD4 T-cells comprising HIV-1 infected CD4 T-cells and uninfected CD4 T-cells, In addition, caspase-1 inhibitors inhibit inflammation, and pyroptosis.
Claims54
A method for the treatment of a patient having an Human Immunodeficiency Virus-1 (HIV-1) infection or suspected of having an HIV-1 infection or having AIDS, the method comprising the step of:
- (a) administering to a patient having an HIV-1 infection or suspected of having an HIV-1 infection or having AIDS a pharmaceutical composition comprising a pharmaceutically effective amount of a caspase-1 inhibitor selected from the group consisting of BACMK (Boc-Asp(Obzl)-CMK, Z-VAD, BocD, LY333531, casputin, Ac-DQMD-CHO (SEQ ID NO:
- 3), CV-1013, VX-740, VX-765, VX-799, IDN-5370, IDN-6556, IDN-6734, IDN-1965, IDN-1529, Z-VAD-fmk, Z-DEVD-CMK (SEQ ID NO:
- 5), Z-DEVD (SEQ ID NO:
- 6), Z-Asp-CH2-DCB, Ac-IETD (SEQ ID NO:
- 8), Ac-VDVAD (SEQ ID NO:
- 9), Ac-DQMD (SEQ ID NO:
- 10), Ac-LEHD (SEQ ID NO:
- 11), Z-WEHD (SEQ ID NO:
- 12), Z-WEHD-fmk (SEQ ID NO:
- 13), Z-WE(OMe)HD(OMe)-fmk (SEQ ID NO:
- 14), Z-YVAD (SEQ ID NO:
- 15), Z-YVAD-fmk (SEQ ID NO:
- 16), Ac-VEID (SEQ ID NO:
- 18), Boc-Phg-Asp-fmk, Boc-(2-F-Phg)-Asp-fmk, Boc-(F3-Val)-Asp-fmk, Ac-Phg-Asp-fmk, Ac-(2-F-Phg)-Asp-fmk, Ac—(F3-Val)-Asp-fmk, Z-Phg-Asp-fmk Z-(2-F-Phg)-Asp-fmk, Z—(F3-Val)-Asp-fmk, Z-Chg-Asp-fmk, Z-(2-Fug)-Asp-fmk, Z-(4-F-Phg)-Asp-fmk, Z-(4-Cl-Phg)-Asp-fmk, Z-(3-Thg)-Asp-fmk, Z-(2-Fua)-Asp-fmk, Z-(2-Tha)-Asp-fmk, Z-(3-Fua)-Asp-fmk, Z-(3-Tha)-Asp-fmk, Z-(3-Cl-Ala)-Asp-fmk, Z—(F3-Ala)-Asp-fmk, Z-(3-F-3-Me-Ala)-Asp-fmk, Z-(3-C1-3—F-Ala)-Asp-fmk, Z-(2-Me-Val)-Asp-fmk, Z-(2-Me-Ala)-Asp-fmk, Z-(2-i-Pr-β-Ala)-Asp-fmk, Z-(3-Ph-β-Ala)-Asp-fmk, Z-(3-CN-Ala)-Asp-fmk, Z-(1-Nal)-Asp-fmk, Z-Cha-Asp-fmk, Z-(3-CF3-Ala)-Asp-fmk, Z-(4-CF3-Phg)-Asp-fmk, Z-(3-Me2N-Ala)-Asp-fmk, Z-(2-Abu)-Asp-fmk, Z-Tle-Asp-fmk, Z-Cpg-Asp-fmk, Z-Cbg-Asp-fmk, Z-Thz-Asp-fmk, Z-(2-Thg)-Asp-fmk, a caspase-1 inhibitor having Formula 1a, 1b, 2, 3, 4, 4.1, 4.2, 4.3, 5, 6, 7, 8, 8.1, 8.2, 9, 9.1, 10, 11, 12, 13, 14, 15, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 17.10, 17.11, 17.12, 17.13, 17.14, 17.15, 17.16, 17.17, 17.18, 17.19, 17.20, 17.21, 17.22, 18A, 18B, 18.1, 18.2, 19A, 19B, 20, 20A, 21, 21A, 22, 22A, 23(I), 23(II), 23(III), 24, 25, 26, 27, 28, 29, 30, 31A, 31B, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
- a compound having formula
- wherein R1 is H and R2 is OH,
- a compound having formula 2,
- wherein R1 is
- and R2 is OH,
- a compound having formula
- wherein R1 is OH and R2 is
- a compound having formula
- wherein R1 is
- and R2 is OAc,
- a compound having formula
- wherein R1 is OAc and R2 is
- a compound having formula
- wherein R is CH═CH—CH3, CH2—CH2—CH3 or CH3,
- a compound having formula
- wherein R is H, R-Methoxy(trifluoromethyl)phenylacetic acid (MTPA) ester or S-MTPA ester,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- a compound having formula
- wherein R is H or OH,
- a compound having formula
- wherein R1 is H and R2 is CH2CH3,
- a compound having formula
- wherein R1 is CH3 and R2 is CH2CH3,
- a compound having formula
- wherein R1 is H and R2 is CH═CH2,
- a compound having formula
- wherein R1 is CH3 and R2 is CH═CH2,
- a compound having formula
- wherein R1 is H or CH3,
- a compound having formula
- wherein * represents a chiral center of the compound,
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- combinations thereof, and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof;
- wherein the patient has CD4 T-cells undergoing pyroptosis;
- and
- whereby the patient is treated.
66 more elements
A method for inhibiting pyroptosis comprising the steps of:
- (a) administering to a patient having cells undergoing pyroptosis a pharmaceutically effective amount of a caspase-1 inhibitor selected from the group consisting of BACMK (Boc-Asp(Obzl)-CMK, Z-VAD, BocD, LY333531, casputin, Ac-DQMD-CHO (SEQ ID NO:
- 3), CV-1013, VX-740, VX-765, VX-799, IDN-5370, IDN-6556, IDN-6734, IDN-1965, IDN-1529, Z-VAD-fmk, Z-DEVD-CMK (SEQ ID NO:
- 5), Z-DEVD (SEQ ID NO:
- 6), Z-Asp-CH2-DCB, Ac-IETD (SEQ ID NO:
- 8), Ac-VDVAD (SEQ ID NO:
- 9), Ac-DQMD (SEQ ID NO:
- 10), Ac-LEHD (SEQ ID NO:
- 11), Z-WEHD (SEQ ID NO:
- 12), Z-WEHD-fmk (SEQ ID NO:
- 13), Z-WE(OMe)HD(OMe)-fmk (SEQ ID NO:
- 14), Z-YVAD (SEQ ID NO:
- 15), Z-YVAD-fmk (SEQ ID NO:
- 16), Ac-VEID (SEQ ID NO:
- 18), Boc-Phg-Asp-fmk, Boc-(2-F-Phg)-Asp-fmk, Boc-(F3—Val)-Asp-fmk, Ac-Phg-Asp-fmk, Ac-(2-F-Phg)-Asp-fmk, Ac—(F3-Val)-Asp-fmk, Z-Phg-Asp-fmk Z-(2-F-Phg)-Asp-fmk, Z—(F3-Val)-Asp-fmk, Z-Chg-Asp-fmk, Z-(2-Fug)-Asp-fmk, Z-(4-F-Phg)-Asp-fmk, Z-(4-Cl-Phg)-Asp-fmk, Z-(3-Thg)-Asp-fmk, Z-(2-Fua)-Asp-fmk, Z-(2-Tha)-Asp-fmk, Z-(3-Fua)-Asp-fmk, Z-(3-Tha)-Asp-fmk, Z-(3-Cl-Ala)-Asp-fmk, Z—(F3-Ala)-Asp-fmk, Z-(3-F-3-Me-Ala)-Asp-fmk, Z-(3-C1-3-F-Ala)-Asp-fmk, Z-(2-Me-Val)-Asp-fmk, Z-(2-Me-Ala)-Asp-fmk, Z-(2-i-Pr-β-Ala)-Asp-fmk, Z-(3-Ph-β-Ala)-Asp-fmk, Z-(3-CN-Ala)-Asp-fmk, Z-(1-Nal)-Asp-fmk, Z-Cha-Asp-fmk, Z-(3-CF3-Ala)-Asp-fmk, Z-(4-CF3-Phg)-Asp-fmk, Z-(3-Me2N-Ala)-Asp-fmk, Z-(2-Abu)-Asp-fmk, Z-Tle-Asp-fmk, Z-Cpg-Asp-fmk, Z-Cbg-Asp-fmk, Z-Thz-Asp-fmk, Z-(2-Thg)-Asp-fmk, a caspase-1 inhibitor having Formula 1a, 1b, 2, 3, 4, 4.1, 4.2, 4.3, 5, 6, 7, 8, 8.1, 8.2, 9, 9.1, 10, 11, 12, 13, 14, 15, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 17.10, 17.11, 17.12, 17.13, 17.14, 17.15, 17.16, 17.17, 17.18, 17.19, 17.20, 17.21, 17.22, 18A, 18B, 18.1, 18.2, 19A, 19B, 20, 20A, 21, 21A, 22, 22A, 23(I), 23(II), 23(III), 24, 25, 26, 27, 28, 29, 30, 31A, 31B, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
- a compound having formula
- wherein R1 is H and R2 is OH,
- a compound having formula
- wherein R1 is
- and R2 is OH,
- a compound having formula
- wherein R1 is OH and R2 is
- a compound having formula
- wherein R1 is
- and R2 is OAc,
- a compound having formula
- wherein R1 is OAc and R2 is
- a compound having formula
- wherein R is CH═CH—CH3, CH2—CH2—CH3 or CH3,
- a compound having formula
- wherein R is H, R-Methoxy(trifluoromethyl)phenylacetic acid (MTPA) ester or S-MTPA ester,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- a compound having formula
- wherein R is H or OH,
- a compound having formula
- wherein R1 is H and R2 is CH2CH3,
- a compound having formula
- wherein R1 is CH3 and R2 is CH2CH3,
- a compound having formula
- wherein R1 is H and R2 is CH═CH2,
- a compound having formula
- wherein R1 is CH3 and R2 is CH═CH2,
- a compound having formula
- wherein R1 is H or CH3,
- a compound having formula
- wherein * represents a chiral center of the compound,
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- combinations thereof, and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof;
- and
- (b) administering to the patient an anti-HIV-1 compound;
- whereby pyroptosis is inhibited.
66 more elements
A method for inhibiting pyroptosis comprising the steps of:
- (a) administering to a patient having cells undergoing pyroptosis a pharmaceutically effective amount of a caspase-1 inhibitor selected from the group consisting of BACMK (Boc-Asp(Obzl)-CMK, Z-VAD, BocD, LY333531, casputin, Ac-DQMD-CHO (SEQ ID NO:
- 3), CV-1013, VX-740, VX-765, VX-799, IDN-5370, IDN-6556, IDN-6734, IDN-1965, IDN-1529, Z-VAD-fmk, Z-DEVD-CMK (SEQ ID NO:
- 5), Z-DEVD (SEQ ID NO:
- 6), Z-Asp-CH2-DCB, Ac-IETD (SEQ ID NO:
- 8), Ac-VDVAD (SEQ ID NO:
- 9), Ac-DQMD (SEQ ID NO:
- 10), Ac-LEHD (SEQ ID NO:
- 11), Z-WEHD (SEQ ID NO:
- 12), Z-WEHD-fmk (SEQ ID NO:
- 13), Z-WE(OMe)HD(OMe)-fmk (SEQ ID NO:
- 14), Z-YVAD (SEQ ID NO:
- 15), Z-YVAD-fmk (SEQ ID NO:
- 16), Ac-VEID (SEQ ID NO:
- 18), Boc-Phg-Asp-fmk, Boc-(2-F-Phg)-Asp-fmk, Boc-(F3—Val)-Asp-fmk, Ac-Phg-Asp-fmk, Ac-(2-F-Phg)-Asp-fmk, Ac—(F3-Val)-Asp-fmk, Z-Phg-Asp-fmk Z-(2-F-Phg)-Asp-fmk, Z—(F3-Val)-Asp-fmk, Z-Chg-Asp-fmk, Z-(2-Fug)-Asp-fmk, Z-(4-F-Phg)-Asp-fmk, Z-(4-Cl-Phg)-Asp-fmk, Z-(3-Thg)-Asp-fmk, Z-(2-Fua)-Asp-fmk, Z-(2-Tha)-Asp-fmk, Z-(3-Fua)-Asp-fmk, Z-(3-Tha)-Asp-fmk, Z-(3-Cl-Ala)-Asp-fmk, Z—(F3-Ala)-Asp-fmk, Z-(3-F-3-Me-Ala)-Asp-fmk, Z-(3-C1-3—F-Ala)-Asp-fmk, Z-(2-Me-Val)-Asp-fmk, Z-(2-Me-Ala)-Asp-fmk, Z-(2-i-Pr-β-Ala)-Asp-fmk, Z-(3-Ph-β-Ala)-Asp-fmk, Z-(3-CN-Ala)-Asp-fmk, Z-(1-Nal)-Asp-fmk, Z-Cha-Asp-fmk, Z-(3-CF3-Ala)-Asp-fmk, Z-(4-CF3-Phg)-Asp-fmk, Z-(3-Me2N-Ala)-Asp-fmnk, Z-(2-Abu)-Asp-fmk, Z-Tle-Asp-fmk, Z-Cpg-Asp-fmk, Z-Cbg-Asp-fmk, Z-Thz-Asp-fmk, Z-(2-Thg)-Asp-fmk, a caspase-1 inhibitor having Formula 1a, 1b, 2, 3, 4, 4.1, 4.2, 4.3, 5, 6, 7, 8, 8.1, 8.2, 9, 9.1, 10, 11, 12, 13, 14, 15, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 17.10, 17.11, 17.12, 17.13, 17.14, 17.15, 17.16, 17.17, 17.18, 17.19, 17.20, 17.21, 17.22, 18A, 18B, 18.1, 18.2, 19A, 19B, 20, 20A, 21, 21A, 22, 22A, 23(I), 23(II), 23(III), 24, 25, 26, 27, 28, 29, 30, 31A, 31B, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
- a compound having formula
- wherein R1 is H and R2 is OH,
- a compound having formula
- wherein R1 is
- and R2 is OH,
- a compound having formula
- wherein R1 is OH and R2 is
- a compound having formula
- wherein R1 is
- and R2 is OAc,
- a compound having formula
- wherein R1 is OAc and R2 is
- a compound having formula
- wherein R is CH═CH—CH3, CH2—CH2—CH3 or CH3,
- a compound having formula
- wherein R is H, R-Methoxy(trifluoromethyl)phenylacetic acid (MTPA) ester or S-MTPA ester,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- wherein R is
- a compound having formula
- a compound having formula
- wherein R is H or OH,
- a compound having formula
- wherein R1 is H and R2 is CH2CH3,
- a compound having formula
- wherein R1 is CH3 and R2 is CH2CH3,
- a compound having formula
- wherein R1 is H and R2 is CH═CH2,
- a compound having formula
- wherein R1 is CH3 and R2 is CH═CH2,
- a compound having formula
- wherein R1 is H or CH3,
- a compound having formula
- wherein * represents a chiral center of the compound,
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- combinations thereof, and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof;
- and
- (b) administering to the patient highly active antiretroviral therapy (HAART);
- wherein pyroptosis is inhibited.
66 more elements
A method for preventing the death of an uninfected or abortively infected CD4 T-cell due to pyroptosis in a population of CD4 T-cells comprising CD4 T-cells productively or abortively infected by Human Immunodeficiency Virus-1 (HIV-1) and uninfected CD4 T-cells, the method comprising the step of contacting the population of CD4 T-cells with a caspase-1 inhibitor selected from the group consisting of BACMK (Boc-Asp(Obzl)-CMK, Z-VAD, BocD, LY333531, casputin, Ac-DQMD-CHO (SEQ ID NO:
- 3), CV-1013, VX-740, VX-765, VX-799, IDN-5370, IDN-6556, IDN-6734, IDN-1965, IDN-1529, Z-VAD-fmk, Z-DEVD-CMK (SEQ ID NO:
- 5), Z-DEVD (SEQ ID NO:
- 6), Z-Asp-CH2-DCB, Ac-IETD (SEQ ID NO:
- 8), Ac-VDVAD (SEQ ID NO:
- 9), Ac-DQMD (SEQ ID NO:
- 10), Ac-LEHD (SEQ ID NO:
- 11), Z-WEHD (SEQ ID NO:
- 12), Z-WEHD-fmk (SEQ ID NO:
- 13), Z-WE(OMe)HD(OMe)-fmk (SEQ ID NO:
- 14), Z-YVAD (SEQ ID NO:
- 15), Z-YVAD-fmk (SEQ ID NO:
- 16), Ac-VEID (SEQ ID NO:
- 18), Boc-Phg-Asp-fmk, Boc-(2-F-Phg)-Asp-fmk, Boc-(F3-Val)-Asp-fmk, Ac-Phg-Asp-fmk, Ac-(2-F-Phg)-Asp-fmk, Ac—(F3-Val)-Asp-fmk, Z-Phg-Asp-fmk Z-(2-F-Phg)-Asp-fmk, Z—(F3-Val)-Asp-fmk, Z-Chg-Asp-fmk, Z-(2-Fug)-Asp-fmk, Z-(4-F-Phg)-Asp-fmk, Z-(4-Cl-Phg)-Asp-fmnk, Z-(3-Thg)-Asp-fmk, Z-(2-Fua)-Asp-fmk, Z-(2-Tha)-Asp-fmk, Z-(3-Fua)-Asp-fmk, Z-(3-Tha)-Asp-fmk, Z-(3-Cl-Ala)-Asp-fmk, Z—(F3-Ala)-Asp-fmk, Z-(3-F-3-Me-Ala)-Asp-fmk, Z-(3-C1-3—F-Ala)-Asp-fmk, Z-(2-Me-Val)-Asp-fmk, Z-(2-Me-Ala)-Asp-fmk, Z-(2-i-Pr-β-Ala)-Asp-fmk, Z-(3-Ph-β3-Ala)-Asp-fmk, Z-(3-CN-Ala)-Asp-fmk, Z-(1-Nal)-Asp-fmk, Z-Cha-Asp-fmk, Z-(3-CF3-Ala)-Asp-fmk, Z-(4-CF3-Phg)-Asp-fmk, Z-(3-Me2N-Ala)-Asp-fmk, Z-(2-Abu)-Asp-fmk, Z-Tle-Asp-fmk, Z-Cpg-Asp-fmk, Z-Cbg-Asp-fmk, Z-Thz-Asp-fmk, Z-(2-Thg)-Asp-fmk, a caspase-1 inhibitor having Formula 1a, 1b, 2, 3, 4, 4.1, 4.2, 4.3, 5, 6, 7, 8, 8.1, 8.2, 9, 9.1, 10, 11, 12, 13, 14, 15, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 17.10, 17.11, 17.12, 17.13, 17.14, 17.15, 17.16, 17.17, 17.18, 17.19, 17.20, 17.21, 17.22, 18A, 18B, 18.1, 18.2, 19A, 19B, 20, 20A, 21, 21A, 22, 22A, 23(I), 23(II), 23(III), 24, 25, 26, 27, 28, 29, 30, 31A, 31B, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
- a compound having formula
- wherein R1 is H and R2 is OH,
- a compound having formula
- wherein R1 is
- and R2 is OH,
- a compound having formula
- wherein R1 is OH and R2 is
- a compound having formula
- wherein R1 is
- and R2 is OAc,
- a compound having formula
- wherein R1 is OAc and R2 is
- a compound having formula
- wherein R is CH═CH—CH3, CH2—CH2—CH3 or CH3,
- a compound having formula
- wherein R is H, R-Methoxy(trifluoromethyl)phenylacetic acid (MTPA) ester or S-MTPA ester,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- wherein R is H or CH3,
- a compound having formula
- a compound having formula
- wherein R is H or OH,
- a compound having formula
- wherein R1 is H and R2 is CH2CH3,
- a compound having formula
- wherein R1 is CH3 and R2 is CH2CH3,
- a compound having formula
- wherein R1 is H and R2 is CH═CH2,
- a compound having formula
- wherein R1 is CH3 and R2 is CH═CH2,
- a compound having formula
- wherein R1 is H or CH3,
- a compound having formula
- wherein * represents a chiral center of the compound,
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- a compound having formula
- combinations thereof, and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof;
- and
- whereby the death of the uninfected or abortively infected CD4 T-cell due to pyroptosis is prevented.
65 more elements
Dependencies are inferred from the claim text.