ABSTRACT
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
Subject(s)
Antiviral Agents , Azetidines , Oxindoles , Respiratory Syncytial Virus Infections , Spiro Compounds , Humans , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/drug therapy , Animals , Oxindoles/chemistry , Oxindoles/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/pharmacokinetics , Spiro Compounds/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/administration & dosage , Azetidines/chemistry , Azetidines/pharmacology , Azetidines/administration & dosage , Azetidines/pharmacokinetics , Pre-Exposure Prophylaxis/methods , Injections, Intramuscular , Indoles/chemistry , Indoles/administration & dosage , Indoles/pharmacology , Injections, Subcutaneous , Respiratory Syncytial Virus, Human/drug effects , Virus Internalization/drug effectsABSTRACT
Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.
Subject(s)
Antiviral Agents , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Virus Replication , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/virology , Animals , Humans , Virus Replication/drug effects , Respiratory Syncytial Virus, Human/drug effects , Sheep , Drug Resistance, Viral , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolism , Viral Proteins/genetics , Lung/virologyABSTRACT
The 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.
