1. Evaluation of potency and metabolic stability of diphyllin-derived Vacuolar-ATPase inhibitors.
- Author
-
Sanford LM, Keiser P, Fujii N, Woods H, Zhang C, Xu Z, Mahajani NS, Cortés JG, Plescia CB, Knipp G, Stahelin RV, Davey R, and Davisson VJ
- Subjects
- Animals, Mice, Structure-Activity Relationship, Humans, Molecular Structure, Ebolavirus drug effects, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Dose-Response Relationship, Drug, Lignans pharmacology, Lignans chemistry, Naphthalenes pharmacology, Naphthalenes chemistry, Naphthalenes pharmacokinetics, Naphthalenes chemical synthesis, Virus Internalization drug effects, Vacuolar Proton-Translocating ATPases antagonists & inhibitors, Vacuolar Proton-Translocating ATPases metabolism, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Antiviral Agents chemical synthesis
- Abstract
Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC
50 values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. The corresponding author is a founder and CSO of Amplified Sciences, Inc and Aromarc Therapeutics, Inc. These companies hold no competing or common interests in the work being submitted for publication. All other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF