title: Design and evaluation of novel interferon lambda analogs with enhanced antiviral activity and improved drug attributes.
abstract: Type III interferons (IFNs) (also called IFN-λ: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4) are critical players in the defense against viral infection of mucosal epithelial cells, where the activity of type I IFNs is weak, and unlike type I IFNs that are associated with severe and diverse side effects, type III IFNs cause minimal side effects due to the highly restricted expression of their receptors, and thus appear to be promising agents for the treatment and prevention of respiratory and gastrointestinal viral infection. However, the antiviral potency of natural type III IFNs is weak compared to type I and, although IFN-λ3 possesses the highest bioactivity among the type III IFNs, IFN-λ1, instead of IFN-λ3, is being developed as a therapeutic drug due to the difficulty to express IFN-λ3 in the prokaryotic expression system. Here, to develop optimal IFN-λ molecules with improved drug attributes, we designed a series of IFN-λ analogs by replacing critical amino acids of IFN-λ1 with the IFN-λ3 counterparts, and vice versa. Four of the designed analogs were successfully expressed in Escherichia coli with high yield and were easily purified from inclusion bodies. Interestingly, all four analogs showed potent activity in inducing the expression of the antiviral genes MxA and OAS and two of them, analog-6 and -7, displayed an unexpected high potency that is higher than that of type I IFN (IFN-α2a) in activating the IFN-stimulated response element (ISRE)-luciferase reporter. Importantly, both analog-6 and -7 effectively inhibited replication of hepatitis C virus in Huh-7.5.1 cells, with an IC50 that is comparable to that of IFN-α2a; and consistent with the roles of IFN-λ in mucosal epithelia, both analogs potently inhibited replication of H3N2 influenza A virus in A549 cells. Together, these studies identified two IFN-λ analogs as candidates to be developed as novel antiviral biologics.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Debin
authors.initials: D
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Proteomics, National Engineering Research Center for Protein Drugs, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Zhao
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Dong
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Psychology, College of Liberal Arts and Social Sciences, University of Houston, Houston, TX, USA.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Zou
authors.affiliation: Prosit Sole Biotechnology, Co., Ltd., Beijing, People's Republic of China.
authors.forename: Hetong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Prosit Sole Biotechnology, Co., Ltd., Beijing, People's Republic of China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Prosit Sole Biotechnology, Co., Ltd., Beijing, People's Republic of China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zou
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000596:Amino Acids / Q000737:chemistry; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D015195:Drug Design; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007372:Interferons / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase
keywords: IFN- λ; IL-28B; IL-29; analog; antiviral; type III interferon