title: Micrococcin P1, a naturally occurring macrocyclic peptide inhibiting hepatitis C virus entry in a pan-genotypic manner.
abstract: Hepatitis C virus (HCV) is considered a major public health concern worldwide. Despite recent advances in curing chronic hepatitis C, unmet medical needs still remain, especially due to the high economic burden of therapies. Accordingly, our study aimed to identify affordable novel HCV inhibitors by screening of natural product compound libraries. We identified micrococcin P1, a macrocyclic peptide antibiotic, inhibiting HCV entry in a pan-genotypic manner with an EC50 range of 0.1-0.5 μM. Micrococcin P1 interfered with HCV entry at an attachment step. Furthermore, micrococcin P1 efficiently inhibited HCV spread by blocking cell-free infection as well as cell-to-cell transmission, without affecting the secretion of infectious virions. Interestingly, the putative molecular target of micrococcin P1 is glycoprotein E2 (IIe-630-Thr), as revealed by selection for viral drug resistance. In addition, micrococcin P1 inhibited sofosbuvir-resistant HCV strains and showed synergy in combination with selected HCV drugs, suggesting an alternative treatment paradigm for patients. In conclusion, we identified micrococcin P1 as specifically inhibiting entry of all HCV genotypes and demonstrated that micrococcin P1 potentially could add value to therapies in combination with current HCV interventions.
authors.affiliation: Hepatitis Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea; Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, South Korea.
authors.forename: Myungeun
authors.initials: M
authors.lastname: Lee
authors.affiliation: Hepatitis Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Yang
authors.affiliation: Hepatitis Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Park
authors.affiliation: Hepatitis Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Jo
authors.affiliation: Hepatitis Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, South Korea.
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Hepatitis Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea. Electronic address: marc.windisch@ip-korea.org.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Windisch
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001430:Bacteriocins / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000187:drug effects; D004357:Drug Synergism; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*; D057074:Virus Release / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001430:Bacteriocins; D010455:Peptides; C009779:micrococcin
keywords: Antiviral inhibitor; HCV entry; Hepatitis C virus; Micrococcin P1; Pan-genotypic inhibitor