Author: Kaushik-Basu, Neerja ; Frick, David N ; Andreev, Ivan A ; Manvar, Dinesh ; Basu, Amartya ; Lukyanenko, Evgeny R ; Kurkin, Alexander V ; Manfroni, Giuseppe ; Altieri, Andrea ; Yerukhimovich, Mark M ; Ratmanova, Nina K ; Belov, Dmitry S ; Barreca, Maria Letizia ; Belov, Grigory M ; Cecchetti, Violetta ; Cevik, Ozge

We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 μM and 4.5 μM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.

24 Nov 2014·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

Structure–Activity Relationships of a Novel Capsid Targeted Inhibitor of HIV-1 Replication

Q2 · CHEMISTRY

Article

Author: Kortagere, Sandhya ; Ptak, Roger G. ; Cocklin, Simon ; Mankowski, Marie K. ; Xu, Jimmy P.

Despite the considerable successes of highly active antiretroviral therapy (HAART) for the treatment of HIV/AIDS, cumulative drug toxicities and the development of multidrug-resistant virus necessitate the search for new classes of antiretroviral agents with novel modes of action. The HIV-1 capsid (CA) protein has been structurally and functionally characterized as a druggable target. We have recently designed a novel small molecule inhibitor I-XW-053 using the hybrid structure based method to block the interface between CA N-terminal domains (NTD-NTD interface) with micromolar affinity. In an effort to optimize and improve the efficacy of I-XW-053, we have developed the structure activity relationship of I-XW-053 compound series using ligand efficiency methods. Fifty-six analogues of I-XW-053 were designed that could be subclassified into four different core domains based on their ligand efficiency values computed as the ratio of binding efficiency (BEI) and surface efficiency (SEI) indices. Compound 34 belonging to subcore-3 showed an 11-fold improvement over I-XW-053 in blocking HIV-1 replication in primary human peripheral blood mononuclear cells (PBMCs). Surface plasmon resonance experiments confirmed the binding of compound 34 to purified HIV-1 CA protein. Molecular docking studies on compound 34 and I-XW-053 to HIV-1 CA protein suggested that they both bind to NTD-NTD interface region but with different binding modes, which was further validated using site-directed mutagenesis studies.

01 Nov 2001·Journal of Medicinal ChemistryQ1 · MEDICINE

Design and Pharmacological Activity of Phosphinic Acid Based NAALADase Inhibitors

Q1 · MEDICINE

Article

Author: Slusher, Barbara S. ; Vitharana, Dil ; Stoermer, Doris ; Ko, Yao-Sen ; Tays, Kevin L. ; Li, Weixing ; Maclin, Keith M. ; Wozniak, Krystyna ; Tsukamoto, Takashi ; Jackson, Paul F. ; Lu, Xi-Chun M.

A novel series of phosphinic acid based inhibitors of the neuropeptidase NAALADase are described in this work. This series of compounds is the most potent series of inhibitors of the enzyme described to date. In addition, we have shown that these compounds are protective in animal models of neurodegeneration. Compound 34 significantly prevented neurodegeneration in a middle cerebral artery occlusion model of cerebral ischemia. In addition, in the chronic constrictive model of neuropathic pain, compound 34 significantly attenuated the hypersensitivity observed with saline-treated animals. These data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Preclinical	US	ESCAPE Bio, Inc.Startup	19 Sep 2023

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