Journal
FRONTIERS IN MICROBIOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2022.896588
Keywords
cellular protease activity; HCV NS3/4A serine protease; protease-activated retention peptide; micro-positron emission tomography; TAT-delta NS3/4A-I-124-FITC probe
Categories
Funding
- National Research Program for Biopharmaceuticals, Ministry of Science and Technology, Taipei, Taiwan
- Kaohsiung Medical University [MOST 110-2320-B-037-027-MY3, MOST 108-2314-B-037-021-MY3, MOST 110-2627-M-037-001, MOST 110-2314-B-037-075-MY2]
- National Kaohsiung University of Science and Technology [NK110I02-2, KMU-DK(B)110005-4, KMU-DK(B)110005, KMU-S110002, KMU-TC111A03-2, KMU-110KK004, KMU-M111011]
- National Sun Yat-sen University [110E9010BA11]
- Kaohsiung Medical University Hospital
- [KMUH108-8R66]
- [KMUH109-9R78]
- [KMUH-DK(B)109001-3]
- [KMUH-DK(B)110005]
- [KMUH-DK(B)110005-1]
- [KMUH-DK(B)110005-2]
- [KMUH-DK(B)110005-3]
- [KMUH-DK(B)110005-4]
- [KMUH110-0R72]
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The study developed a protease-activatable retention probe for tracking the activity of hepatitis C virus NS3/4A protease. This probe can be detected using positron emission topography (PET) imaging to monitor the distribution and activity of NS3/4A protease.
Hepatitis C virus (HCV) NS3/4A protease is an attractive target for direct-acting antiviral agents. Real-time tracking of the NS3/4A protease distribution and activity is useful for clinical diagnosis and disease management. However, no approach has been developed that can systemically detect NS3/4A protease activity or distribution. We designed a protease-activatable retention probe for tracking HCV NS3/4A protease activity via positron emission topography (PET) imaging. A cell-penetrating probe was designed that consisted of a cell-penetrating Tat peptide, HCV NS3/4A protease substrate, and a hydrophilic domain. The probe was labeled by fluorescein isothiocyanate (FITC) and I-124 in the hydrophilic domain to form a TAT-delta NS3/4A-I-124-FITC probe. Upon cleavage at NS3/4A substrate, the non-penetrating hydrophilic domain is released and accumulated in the cytoplasm allowing PET or optical imaging. The TAT-delta NS3/4A-FITC probe selectively accumulated in NS3/4A-expressing HCC36 (NS3/4A-HCC36) cells/tumors and HCV-infected HCC36 cells. PET imaging showed that the TAT-delta NS3/4A-I-124-FITC probe selectively accumulated in the NS3/4A-HCC36 xenograft tumors and liver-implanted NS3/4A-HCC36 tumors, but not in the control HCC36 tumors. The TAT-delta NS3/4A-I-124-FITC probe can be used to represent NS3/4 protease activity and distribution via a clinical PET imaging system allowing. This strategy may be extended to detect any cellular protease activity for optimization the protease-based therapies.
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