CD4-mimetic inhibitors of HIV-1 entry and methods of use thereof
Inventors
Sodroski, Joseph • LaLonde, Judith M. • Smith, III, Amos B. • Kwong, Peter D. • Kwon, Young Do • Jones, David M. • Sun, Alexander W. • Courter, Joel R. • Soeta, Takahiro • Kobayashi, Toyoharu • Princiotto, Amy M. • Wu, Xueling • Mascola, John R. • Schon, Arne • Freire, Ernesto • Madani, Navid • Le-Khac, Matthew • Hendrickson, Wayne A. • PARK, Jongwoo
Assignees
Columbia University in the City of New York • Dana Farber Cancer Institute Inc • Johns Hopkins University • Bryn Mawr College • University of Pennsylvania Penn • US Department of Health and Human Services
Publication Number
US-9403763-B2
Publication Date
2016-08-02
Expiration Date
2032-12-14
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Abstract
Described herein are small-molecule mimics of CD4, which both enter the Phe43 cavity and target Asp368 of gp120, the HIV-1 envelope protein. Also described herein are methods of using these compounds to inhibit the transmission or progression of HIV infection. These compounds exhibit antiviral potency greater than that of a known antiviral, NBD-556, with 100% breadth against clade B and C viruses. Importantly, the compounds do not activate HIV infection of CD4-negative, CCR5-positive cells, in contrast to NBD-556.
Core Innovation
The invention relates to small-molecule mimics of CD4 that target the conserved Phe43 cavity and Asp368 residue of gp120, the HIV-1 envelope protein. These compounds exhibit antiviral potency greater than a known antiviral, NBD-556, with 100% breadth against clade B and C viruses and do not activate HIV infection of CD4-negative, CCR5-positive cells, unlike NBD-556.
HIV-1 entry involves the attachment of the virus to the host cell via gp120 binding to the CD4 receptor, triggering a conformational change that permits chemokine receptor binding and viral entry. The highly conserved gp120-CD4 interface includes the Phe43 cavity and the electrostatic interaction between Arg59CD4 and Asp368gp120, critical for binding. Prior small molecules such as NBD-556 bind the Phe43 cavity but fail to mimic the Asp368gp120–Arg59CD4 interaction effectively, leaving an unmet need for inhibitors that mimic both gp120-CD4 hotspots with improved antiviral and thermodynamic properties.
The invention addresses this problem by using a structure-based design strategy and virtual screening to identify compounds, including analogs like AWS-I-169 and DMJ-I-228, employing a trans-1,2-disubstituted indane scaffold to direct a guanidinium group toward Asp368gp120. These compounds form specific electrostatic and water-mediated hydrogen bonding interactions with Asp368gp120 and demonstrate improved binding affinity, antiviral activity, and a more favorable thermodynamic signature compared to previous compounds. They effectively inhibit HIV-1 entry across major clades and avoid unwanted enhancement of viral infectivity in CD4-deficient cells.
Claims Coverage
The patent includes one independent compound claim defining a broad chemical formula and one independent method claim for using these compounds to affect HIV gp120 activity and infection.
Compound with specific formula targeting gp120
A compound of Formula VII or related formulas characterized by specific substituents R1 through R5 and integers m and n, designed to bind specifically to the Phe43 cavity and interact with Asp368gp120 of the HIV gp120 protein.
Pharmaceutical composition comprising the compound
A pharmaceutical composition that includes a compound of Formula VII or a pharmaceutically acceptable salt thereof along with a pharmaceutically acceptable carrier for administration.
Method of modulating HIV gp120 activity and inhibiting HIV transmission and progression
A method of activating HIV envelope glycoprotein gp120, inhibiting the transmission of HIV to cells, or inhibiting the progression of HIV infection in cells by contacting HIV with an effective amount of a compound of Formula VII or its pharmaceutically acceptable salt. This method can further include contacting HIV with an exogenous ligand mimicking the chemokine receptor expressed on the target cell.
The independent claims cover a class of chemical compounds with defined substituents that selectively bind HIV gp120, pharmaceutical compositions containing these compounds, and methods of using these compounds to activate gp120 and inhibit HIV transmission and progression by targeting specific gp120 hotspots.
Stated Advantages
The compounds exhibit antiviral potency greater than previously known antivirals such as NBD-556, with 100% breadth against clade B and C HIV-1 viruses.
The compounds do not enhance HIV infection of CD4-negative, CCR5-positive cells, avoiding a drawback of known compounds like NBD-556.
Improved binding affinity resulting from mimicking both the Phe43 cavity and Asp368gp120 hotspots.
Enhanced thermodynamic properties, including reduced unfavorable entropic penalties for certain compounds, suggesting suitability for further development.
High-resolution crystal structures provide a novel structural paradigm for continued design and development of this class of HIV-1 entry inhibitors.
Documented Applications
Use of the disclosed compounds to activate the HIV envelope glycoprotein gp120.
Methods for inhibiting the transmission of HIV to cells by administering the compounds to HIV.
Methods for inhibiting the progression of HIV infection in cells using the compounds.
Combination therapies involving the compounds and exogenous ligands that mimic chemokine receptors CCR5 or CXCR4 to inhibit HIV transmission or progression.
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