Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan 30;10(2):215-220.
doi: 10.1021/acsmedchemlett.8b00633. eCollection 2019 Feb 14.

An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors

Tyler A Wilson  1 , Pratibha C Koneru  2 , Stephanie V Rebensburg  2 , Jared J Lindenberger  2 , Matthew J Kobe  3 , Nicholas T Cockroft  1 , Daniel Adu-Ampratwum  1 , Ross C Larue  3 , Mamuka Kvaratskhelia  2 , James R Fuchs  1
Affiliations

An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors

Tyler A Wilson et al. ACS Med Chem Lett. .

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 6l 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, 6l potently inhibited HIV-1NL4-3 (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 Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of the representative ALLINI compounds BIB-II and KF116.
Scheme 1
Scheme 1. Synthesis of Isoquinoline Analogues 6a–l
Scheme 2
Scheme 2. Synthesis of Compound 9
Figure 2
Figure 2
Crystal structures of 6b (magenta) and 6l (green) bound to the CCD dimer (subunits 1 and 2 are colored orange and cyan, respectively).
Scheme 3
Scheme 3. Degradation of 6i under Thermal Conditions
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kessl J. J.; Kutluay S. B.; Townsend D.; Rebensburg S.; Slaughter A.; Larue R. C.; Shkriabai N.; Bakouche N.; Fuchs J. R.; Bieniasz P. D.; Kvaratskhelia M. HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis. Cell 2016, 166, 1257–1268. 10.1016/j.cell.2016.07.044. - DOI - PMC - PubMed
    1. Passos D. O.; Li M.; Yang R.; Rebensburg S. V.; Ghirlando R.; Jeon Y.; Shkriabai N.; Kvaratskhelia M.; Craigie R.; Lyumkis D. Cryo-EM Structures and Atomic Model of the HIV-1 Strand Transfer Complex Intasome. Science 2017, 355, 89–92. 10.1126/science.aah5163. - DOI - PMC - PubMed
    1. McColl D. J.; Chen X. Strand Transfer Inhibitors of HIV-1 Integrase: Bringing IN a New Era of Antiretroviral Therapy. Antiviral Res. 2010, 85, 101–118. 10.1016/j.antiviral.2009.11.004. - DOI - PubMed
    1. Summa V.; Petrocchi A.; Bonelli F.; Crescenzi B.; Donghi M.; Ferrara M.; Fiore F.; Gardelli C.; Gonzalez Paz O.; Hazuda D. J.; Jones P.; Kinzel O.; Laufer R.; Monteagudo E.; Muraglia E.; Nizi E.; Orvieto F.; Pace P.; Pescatore G.; Scarpelli R.; Stillmock K.; Witmer M. V.; Rowley M. Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection. J. Med. Chem. 2008, 51, 5843–5855. 10.1021/jm800245z. - DOI - PubMed
    1. Raffi F.; Wainberg M. A. Multiple Choices for HIV Therapy with Integrase Strand Transfer Inhibitors. Retrovirology 2012, 9, 110–113. 10.1186/1742-4690-9-110. - DOI - PMC - PubMed