Biomaterial Database

Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases. 2023

Victoria A Kleiner, and Thierry O Fischmann, and John A Howe, and Douglas C Beshore, and Michael J Eddins, and Yan Hou, and Todd Mayhood, and Daniel Klein, and Debbie D Nahas, and Bob J Lucas, and He Xi, and Edward Murray, and Daphne Y Ma, and Krista Getty, and Rachel Fearns

Department of Virology, Immunology & Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are related RNA viruses responsible for severe respiratory infections and resulting disease in infants, elderly, and immunocompromised adults1-3. Therapeutic small molecule inhibitors that bind to the RSV polymerase and inhibit viral replication are being developed, but their binding sites and molecular mechanisms of action remain largely unknown4. Here we report a conserved allosteric inhibitory site identified on the L polymerase proteins of RSV and HMPV that can be targeted by a dual-specificity, non-nucleoside inhibitor, termed MRK-1. Cryo-EM structures of the inhibitor in complexes with truncated RSV and full-length HMPV polymerase proteins provide a structural understanding of how MRK-1 is active against both viruses. Functional analyses indicate that MRK-1 inhibits conformational changes necessary for the polymerase to engage in RNA synthesis initiation and to transition into an elongation mode. Competition studies reveal that the MRK-1 binding pocket is distinct from that of a capping inhibitor with an overlapping resistance profile, suggesting that the polymerase conformation bound by MRK-1 may be distinct from that involved in mRNA capping. These findings should facilitate optimization of dual RSV and HMPV replication inhibitors and provide insights into the molecular mechanisms underlying their polymerase activities.

UI	MeSH Term	Description	Entries
D007223	Infant	A child between 1 and 23 months of age.	Infants
D012141	Respiratory Tract Infections	Invasion of the host RESPIRATORY SYSTEM by microorganisms, usually leading to pathological processes or diseases.	Respiratory System Infections,Upper Respiratory Tract Infection,Upper Respiratory Tract Infections,Infections, Respiratory,Infections, Respiratory Tract,Infections, Upper Respiratory,Infections, Upper Respiratory Tract,Respiratory Infections,Upper Respiratory Infections,Infection, Respiratory System,Infection, Respiratory Tract,Respiratory Infection, Upper,Respiratory System Infection,Respiratory Tract Infection
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328	Adult	A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available.	Adults
D000368	Aged	A person 65 years of age or older. For a person older than 79 years, AGED, 80 AND OVER is available.	Elderly
D012324	RNA-Dependent RNA Polymerase	An enzyme that catalyses RNA-template-directed extension of the 3'- end of an RNA strand by one nucleotide at a time, and can initiate a chain de novo. (Enzyme Nomenclature, 1992, p293)	Nucleoside-Triphosphate:RNA Nucleotidyltransferase (RNA-directed),RNA Replicase,RNA-Dependent RNA Replicase,RNA-Directed RNA Polymerase,RNA Dependent RNA Polymerase,RNA Dependent RNA Replicase,RNA Directed RNA Polymerase,RNA Polymerase, RNA-Dependent,RNA Polymerase, RNA-Directed,RNA Replicase, RNA-Dependent,Replicase, RNA,Replicase, RNA-Dependent RNA
D012333	RNA, Messenger	RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.	Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D018113	Respiratory Syncytial Virus, Human	The type species of PNEUMOVIRUS and an important cause of lower respiratory disease in infants and young children. It frequently presents with bronchitis and bronchopneumonia and is further characterized by fever, cough, dyspnea, wheezing, and pallor.	HRSV Human respiratory syncytial virus,Human respiratory syncytial virus,human RSV,RSV, human,human RSVs
D029121	Metapneumovirus	A genus of the subfamily PNEUMOVIRINAE, containing two members: Turkey rhinotracheitis virus and a human Metapneumovirus. Virions lack HEMAGGLUTININ and NEURAMINIDASE.	Avian Metapneumovirus,Avian Pneumovirus,Human Metapneumovirus,Metapneumovirus, Avian,Metapneumovirus, Human,Pneumovirus, Avian,Rhinotracheitis Virus, Turkey,Turkey Rhinotracheitis Virus,Human Metapneumoviruses,Metapneumoviruses,Metapneumoviruses, Human