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Targeted inhibition of hantavirus replication and intracranial pathogenesis by a chimeric protein-delivered siRNA.
- Source :
-
Antiviral research [Antiviral Res] 2017 Nov; Vol. 147, pp. 107-115. Date of Electronic Publication: 2017 Oct 07. - Publication Year :
- 2017
-
Abstract
- Hantavirus (HV) infection, which underlies hantavirus hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome, remains to be a severe clinical challenge. Here, we synthesized small interfering RNAs (siRNAs) that target the encoding sequences of HV strain 76-118, and validated their inhibitory role in virus replication in HV-infected monkey kidney Vero E6 cells. A chimeric protein, 3G1-Cκ-tP, consisting of a single-chain antibody fragment (3G1) against the HV surface envelop glycoprotein, the constant region of human immunoglobulin κ chain (Cκ), and truncated protamine (amino acids 8-29, tP), was further generated. The fusion protein showed high affinity to HV antigen on the infected cell membrane, and internalized through clathrin-mediated endocytosis; it bound to siRNAs via the basic nucleic acid-rich protamine fragment, leading to their specific delivery into HV-infected cells and efficient inhibition of virus replication. An encephalitis mouse model was established via intracranial HV administration. Intraperitoneal injection of siRNAs complexed with 3G1-Cκ-tP achieved specific distribution of siRNAs in HV-infected brain cells, significantly reduced HV antigen levels, and effective protection from HV infection-derived animal death. These results provide a compelling rationale for novel therapeutic protocols designed for HV infection and related disorders.<br /> (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Animals, Newborn
Antigens, Viral metabolism
Chlorocebus aethiops
Disease Models, Animal
Hemorrhagic Fever with Renal Syndrome drug therapy
Hemorrhagic Fever with Renal Syndrome pathology
Humans
Mice
Mice, Inbred BALB C
Protein Binding
RNA Interference
RNA, Small Interfering administration & dosage
RNA, Small Interfering chemistry
RNA, Small Interfering genetics
Recombinant Proteins administration & dosage
Recombinant Proteins genetics
Recombinant Proteins pharmacology
Single-Chain Antibodies genetics
Vero Cells
Viral Envelope Proteins genetics
Viral Load drug effects
Drug Delivery Systems
Orthohantavirus drug effects
Hemorrhagic Fever with Renal Syndrome virology
RNA, Small Interfering pharmacology
Virus Replication drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9096
- Volume :
- 147
- Database :
- MEDLINE
- Journal :
- Antiviral research
- Publication Type :
- Academic Journal
- Accession number :
- 29017779
- Full Text :
- https://doi.org/10.1016/j.antiviral.2017.10.005