HIV-1 capsid protein degrading agent based on hydrophobic tag technology and preparation method and application thereof
The HIV-1 capsid protein degrader synthesized using hydrophobic tagging technology solves the stability and activity problems of existing regulators, achieving efficient degradation of HIV-1 capsid protein and exhibiting significant antiviral activity and potential application value.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG UNIV
- Filing Date
- 2023-09-11
- Publication Date
- 2026-06-09
AI Technical Summary
Existing HIV-1 capsid protein modulators such as PF74 suffer from poor metabolic stability and low pharmacological activity, and are prone to inducing drug resistance, making it difficult to effectively inhibit HIV-1 viral replication and infection.
Novel HIV-1 capsid protein degraders were synthesized using hydrophobic tagging technology. By mimicking the misfolded protein structure, the target protein was degraded via the proteasome pathway. Compounds with different hydrophobic groups, including those with Formula I and Formula II structures, were designed and synthesized. Their synthetic routes were optimized to improve metabolic stability and antiviral activity.
The compounds IA-2b, IA-2l, IA-2n, and IA-2p achieved efficient degradation of HIV-1 capsid protein. They exhibited significant anti-HIV-1 activity at the submicromolar level and have potential for further research and application. The degradation effect may be achieved through the proteasome pathway and other pathways.
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Figure CN117384240B_ABST
Abstract
Claims
1. An HIV-1 capsid protein degrading agent based on hydrophobic tagging technology, characterized in that, It has the structure shown in Equation I or Equation II: Wherein, R1 is H or F; R2 is a linker; R3 is H or a hydrophobic group; The linker comprises compounds with the following general structural formula: ； The hydrophobic groups include compounds with the following general structural formulas a~h: 。 2. The HIV-1 capsid protein degrader based on hydrophobic tag technology as described in claim 1, characterized in that, It is one of the compounds having the following structures: 。 3. The preparation method of the HIV-1 capsid protein degrader based on hydrophobic tag technology as described in claim 2, comprising the following steps: Synthesis of intermediates a-6 and b-6: Starting with N-Boc-L-3,5-difluoro-phenylalanine a-1 and N-Boc-L-phenylalanine b-1, respectively, an amide condensation reaction was carried out with N-methyl-4-aminoanisole in dichloromethane to generate intermediates a-2 and b-2. Subsequently, using dichloromethane as the reaction solvent, the Boc group was removed by reaction with trifluoroacetic acid to generate intermediates a-3 and b-3. Then, an amide condensation reaction was carried out with bromoacetic acid in dichloromethane to generate intermediates a-4 and b-4. Next, a nucleophilic substitution reaction was carried out with tert-butyl 3-oxo-1-piperazincarboxylate in tetrahydrofuran via sodium hydride to obtain intermediates a-5 and b-5. Finally, the Boc group was removed by trifluoroacetic acid to obtain the key intermediates a-6 and b-6. The synthetic routes for intermediates a-6 and b-6 are as follows: Reagents and conditions: (i) N-methyl-4-aminoanisole, HATU, DIEA, dichloromethane, 0ºC to room temperature; (ii) trifluoroacetic acid, dichloromethane, 0ºC to room temperature; (iii) bromoacetic acid, HATU, DIEA, dichloromethane, 0ºC to room temperature; (iv) 3-oxo-1-piperazinic acid tert-butyl ester, sodium hydride, tetrahydrofuran, 0ºC; (v) trifluoroacetic acid, dichloromethane, 0ºC to room temperature; Synthesis of compounds IA-(1a-1j) and IA-(2a-2m, 2o-2q) of Formula I: Using dichloromethane as a solvent, a-6 and b-6 react with tert-butyl 4-(chlorosulfonyl)phenylcarbamate in the presence of triethylamine to obtain aI-7 and bI-7; subsequently, the Boc group is removed by reaction with trifluoroacetic acid in dichloromethane to obtain the key intermediates aI-8 and bI-8; then, aI-(9a-9j) is obtained by reaction with N-Boc alkylamine acids of different lengths in dichloromethane through a condensation reaction; the Boc group is removed by reaction with trifluoroacetic acid in dichloromethane to obtain IA-(1a-1j); finally, IA-(2a-2m, 2o-2q) is obtained by amide condensation reaction with different hydrophobic groups. The synthetic routes for compounds IA-(1a-1j) and IA-(2a-2m, 2o-2q) of Formula I are as follows: Reagents and conditions: (i) tert-butyl 4-(chlorosulfonyl)phenylcarbamate, triethylamine, dichloromethane, room temperature; (ii) trifluoroacetic acid, dichloromethane, 0ºC to room temperature; (iii) N-Boc alkylamines with different substitutions, HATU, DIEA, dichloromethane, 0ºC to 70ºC; (iv) trifluoroacetic acid, dichloromethane, 0ºC to room temperature; (v) carboxyl groups containing different hydrophobic groups, HATU, DIEA, dichloromethane, 0ºC to room temperature; Synthesis of compound IA-2n of formula I: aI-8 reacts with monomethyl glutarate in dichloromethane via an amide condensation reaction to obtain aI-9n; then undergoes ester hydrolysis with lithium hydroxide in tetrahydrofuran and water to obtain IA-1n; finally, it undergoes an amide condensation reaction with norbornene-2-methylamine to obtain IA-2n; The synthetic route for compound IA-2n of formula I is as follows: Reagents and conditions: (i) Monomethyl glutarate, HATU, DIEA, dichloromethane, 0ºC to 70ºC; (ii) Lithium hydroxide, tetrahydrofuran, water, room temperature; (iii) Norbornene-2-methylamine, HATU, DIEA, dichloromethane, 0ºC to room temperature; Synthesis of compounds IIA-(1a-1j) and IIA-(2a-2j) of formula II: Starting from a-6 and b-6, methyl 4-(chlorosulfonyl)benzoate was condensed in dichloromethane to generate aII-7 and bII-7; then, in the presence of lithium hydroxide, the compounds were hydrolyzed in tetrahydrofuran and water to obtain the key intermediates aII-8 and bII-8; then, aII-(9a-9j) was obtained by condensation reaction with N-Boc alkyl diamines of different lengths in dichloromethane; then, the Boc group was removed by trifluoroacetic acid in dichloromethane to obtain IIA-(1a-1j); finally, IIA-(2a-2j) was obtained by amide condensation reaction with different hydrophobic groups. The synthetic routes for compounds IIA-(1a-1j) and IIA-(1a-1j) of formula II are as follows: Reagents and conditions: (i) methyl 4-(chlorosulfonyl)benzoate, triethylamine, dichloromethane, room temperature; (ii) lithium hydroxide, tetrahydrofuran, water, room temperature; (iii) N-Boc alkyl diamines with different substitutions, HATU, DIEA, dichloromethane, 0ºC to room temperature; (iv) trifluoroacetic acid, dichloromethane, 0ºC to room temperature; (v) carboxyl groups with different hydrophobic groups, HATU, DIEA, dichloromethane, 0ºC to room temperature.
4. The use of the HIV-1 capsid protein degrader based on hydrophobic tagging technology as described in any one of claims 1-2 in the preparation of anti-HIV-1 drugs.
5. An anti-HIV-1 pharmaceutical composition comprising an HIV-1 capsid protein degrader based on hydrophobic tagging technology as described in any one of claims 1-2 and one or more pharmaceutically acceptable carriers or excipients.