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Open AccessCommunication

Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability

Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Rooms 10307, 10309, and 10315, 245 North 15th Street, Philadelphia, PA 19102, USA
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Antonio Carta
Molecules 2020, 25(6), 1430; https://doi.org/10.3390/molecules25061430
Received: 28 February 2020 / Revised: 18 March 2020 / Accepted: 19 March 2020 / Published: 21 March 2020
(This article belongs to the Special Issue Antiviral Agents)
Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this. View Full-Text
Keywords: HIV-1 entry inhibitor; metabolic stability; docking; antiviral; surface plasmon resonance; Cyp P450 HIV-1 entry inhibitor; metabolic stability; docking; antiviral; surface plasmon resonance; Cyp P450
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MDPI and ACS Style

Karadsheh, R.; Meuser, M.E.; Cocklin, S. Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability. Molecules 2020, 25, 1430.

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