Author: Tan, Eric ; Jonckers, Tim H. M. ; Alcázar, Jesus ; Stoops, Bart ; Yin, Yanting ; Carbajo, Rodrigo J. ; Lutter, Ferdinand H. ; Rigaux, Peter ; Martinez, Carol ; Cooymans, Ludwig ; Roymans, Dirk ; Tran, Minh T. ; Jacoby, Edgar ; Hu, Lili ; van Vlijmen, Herman ; Grosse, Sandrine ; Yu, Xiaodi ; Pieters, Serge ; Sharma, Sujata

Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase inhibitors (NNI) have emerged as a promising asset for which our group previously disclosed JNJ-8003 with potent in vitro antiviral activity and pronounced in vivo efficacy. In this work, a structural-guided design to modify the linker vector of JNJ-8003 resulted in the identification of 2-oxacyclo pyridine-containing derivatives whose various ring closing strategies are described. In addition, bioisosteric replacement of an amide bond with triazole retained potency, and cryo-electron microscopy (cryo-EM) confirmed binding in the capping domain. Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters.

Communications Biology

Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor

Article

Author: Miller, Robyn ; Bhaumik, Anusarka ; Patrick, Aaron ; Jonckers, Tim H M ; Decroly, Etienne ; Roymans, Dirk ; Rigaux, Peter ; Anson, Brandon ; Sutto-Ortiz, Priscila ; Verheyen, Nick ; Shareef, Afzaal ; Van Vlijmen, Herman ; Abeywickrema, Pravien ; Piassek, Madison ; Behera, Ishani ; Adhikary, Suraj ; Yu, Xiaodi ; Fung, Amy ; Ysebaert, Nina ; Herschke, Florence ; McLellan, Jason S ; Grosse, Sandrine ; Jacoby, Edgar ; De Bruyn, Suzanne ; Sharma, Sujata ; Carbajo, Rodrigo J ; Bonneux, Brecht ; Pham, Quyen ; Fearns, Rachel ; Jin, Zhinan

AbstractThe respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.

100 Deals associated with JNJ-8003

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Syncytial Virus Infections	Preclinical	CN	Johnson & Johnson Pharmaceuticals Co., Ltd.	21 Oct 2023

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

JNJ-8003

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation