6EB2

HIV-1 Integrase Catalytic Core Domain Complexed with Allosteric Inhibitor (2S)-[1-(1-benzyl-1H-pyrazol-4-yl)-3-(3,4-dihydro-2H-1-benzopyran-6-yl)isoquinolin-4-yl](tert-butoxy)acetic acid

Summary for 6EB2

• Entry DOI: 10.2210/pdb6eb2/pdb
• Descriptor: Integrase, (2S)-[1-(1-benzyl-1H-pyrazol-4-yl)-3-(3,4-dihydro-2H-1-benzopyran-6-yl)isoquinolin-4-yl](tert-butoxy)acetic acid (3 entities in total)
• Functional Keywords: hiv, integrase, inhibitor, allosteric, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 20880.43

Authors

Lindenberger, J.J.,Kobe, M.,Kvaratskhelia, M. (deposition date: 2018-08-03, release date: 2019-03-06, Last modification date: 2023-10-11)

Primary citation

Wilson, T.A.,Koneru, P.C.,Rebensburg, S.V.,Lindenberger, J.J.,Kobe, M.J.,Cockroft, N.T.,Adu-Ampratwum, D.,Larue, R.C.,Kvaratskhelia, M.,Fuchs, J.R.
An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors.
ACS Med Chem Lett, 10:215-220, 2019

PubMed Abstract: Allosteric HIV-1 integrase inhibitors (ALLINIs) are a new class of potential antiretroviral therapies with a unique mechanism of action and drug resistance profile. To further extend this class of inhibitors via a scaffold hopping approach, we have synthesized a series of analogues possessing an isoquinoline ring system. Lead compound binds in the v-shaped pocket at the IN dimer interface and is highly selective for promoting higher-order multimerization of inactive IN over inhibiting IN-LEDGF/p75 binding. Importantly, potently inhibited HIV-1 (A128T IN), which confers marked resistance to archetypal quinoline-based ALLINIs. Thermal degradation studies indicated that at elevated temperatures the acetic acid side chain of specific isoquinoline derivatives undergo decarboxylation reactions. This reactivity has implications for the synthesis of various ALLINI analogues.

PubMed: 30783506
DOI: 10.1021/acsmedchemlett.8b00633

Experimental method

X-RAY DIFFRACTION (2.493 Å)