A target site for template-based design of measles virus entry inhibitors.
Measles virus (MV) constitutes a principal cause of worldwide mortality, accounting for almost 1 million deaths annually. Although a live-attenuated vaccine protects against MV, vaccination efficiency of young infants is low because of interference by maternal antibodies. Parental concerns about vaccination safety further contribute to waning herd immunity in developed countries, resulting in recent MV outbreaks. The development of novel antivirals that close the vaccination gap in infants and silence viral outbreaks is thus highly desirable. We previously identified a microdomain in the MV fusion protein (F protein) that is structurally conserved in the paramyxovirus family and constitutes a promising target site for rationally designed antivirals. Here we report the template-based development of a small-molecule MV inhibitor, providing proof-of-concept for our approach. This lead compound specifically inhibits fusion and spread of live MV and MV glycoprotein-induced membrane fusion. The inhibitor induces negligible cytotoxicity and does not interfere with receptor binding or F protein biosynthesis or transport but prevents F protein-induced lipid mixing. Mutations in the postulated target site alter viral sensitivity to inhibition. In silico docking of the compound in this microdomain suggests a binding model that is experimentally corroborated by a structure-activity analysis of the compound and the inhibition profile of mutated F proteins. A second-generation compound designed on the basis of the interaction model shows a 200-fold increase in antiviral activity, creating the basis for novel MV therapeutics. This template-based design approach for MV may be applicable to other clinically relevant members of the paramyxovirus family.
Plemper
Richard K
RK
Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Erlandson
Karl J
KJ
Lakdawala
Ami S
AS
Sun
Aiming
A
Prussia
Andrew
A
Boonsombat
Jutatip
J
Aki-Sener
Esin
E
Yalcin
Ismail
I
Yildiz
Ilkay
I
Temiz-Arpaci
Ozlem
O
Tekiner
Betul
B
Liotta
Dennis C
DC
Snyder
James P
JP
Compans
Richard W
RW
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002459:Cell Fusion; D002522:Chlorocebus aethiops; D015195:Drug Design; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008459:Measles virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D008958:Models, Molecular; D017354:Point Mutation; D011485:Protein Binding; D014162:Transfection; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D010948:Viral Plaque Assay / Q000379:methods
D000998:Antiviral Agents; D006023:Glycoproteins; D008164:Luminescent Proteins; D014759:Viral Envelope Proteins