Bacteriophage PRD1 as a nanoscaffold for drug loading

Journal article

Viruses are very attractive biomaterials owing to their capability as nanocarriers of genetic material. Efforts have been made to functionalize self-assembling viral protein capsids on their exterior or interior to selectively take up different payloads. PRD1 is a double-stranded DNA bacteriophage comprising an icosahedral protein outer capsid and an inner lipidic vesicle. Here, we report the three-dimensional structure of PRD1 in complex with the antipsychotic drug chlorpromazine (CPZ) by cryo-electron microscopy. We show that the jellyrolls of the viral major capsid protein P3, protruding outwards from the capsid shell, serve as scaffolds for loading heterocyclic CPZ molecules. Additional X-ray studies and molecular dynamics simulations show the binding modes and organization of CPZ molecules when complexed with P3 only and onto the virion surface. Collectively, we provide a proof of concept for the possible use of the lattice-like organisation and the quasi-symmetric morphology of virus capsomers for loading heterocyclic drugs with defined properties.This study was supported by the Agencia Estatal de Investigacion (Spain) for project RTI2018-095700-B-I00 (NGAA), for project RTI2018-099592-B-C22 (GJO), and for project FEDER MINECO PGC2018-099857-B-I00 (FMG) and by the Basque Departamento de Educación, Política Lingüística y Cultura for projects PRE_2016_2_0151 (ISP), PRE_2018_1_0102 (AM-C) and IT1264-19 (FMG). DR and NGAA are members of the Spanish Network of Excellence in Physical Virology – FIS2017-90701-REDT. We also thank the Agencia Estatal de Investigacion for the Severo Ochoa Excellence Accreditation to the CIC bioGUNE (SEV-2016-0644). HMED was supported by Wellcome (Grant: ALR00750). DIS was supported by the MRC (MR/N00065X/1).Peer reviewe

Authors: Duyvesteyn, HME; Santos-Pérez, I; Peccati, F; Martinez-Castillo, A; Walter, TS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: Nanoscale
• Volume: 13
• Issue: 47
• Pages: 19875-19883
• Publication date: 2021-12-13
• DOI: 10.1039/d1nr04153c
• EISSN: 2040-3372
• ISSN: 2040-3364
• Language: English
• Keywords: Bacteriophage; Engineering; Nanotechnology; Nanocarriers; Materials science; Genetics; Drug delivery; Biochemical engineering; Biology