Dataset Information

Nonimmunogenetic Viral Capsid Carrier with Cancer Targeting Activity.

ABSTRACT: Although protein nanoparticles (PNPs) (e.g., viral capsids) capable of delivering a broad range of drug agents have shown distinctive advantages over synthetic nanomaterials, PNPs have an intrinsic drawback that hampers their clinical application, that is, potential immunogenicity. Here, a novel method for resolving the immunogenicity problem of PNPs, which is based on the genetic presentation of albumin-binding peptides (ABPs) on the surface of PNP, is reported. ABPs are inserted into the surface of a viral capsid (hepatitis B virus capsid/HBVC) while preserving the native self-assembly function of HBVC. The ABPs effectively gather human serum albumins around HBVC and significantly reduce both inflammatory response and immunoglobulin titer in live mice compared to ABP-free HBVC. Furthermore, ABP-conjugated HBVCs remain within tumors for a longer period than HBVCs conjugated to tumor cell receptor-bindingpeptides, indicating that the ABPs are also capable of enhancing tumor-targeting performance. Although applied to HBVC for proof of concept, this novel approach may provide a general platform for resolving immunogenicity and cancer-targeting problems of PNPs, which enables the development of a variety of PNP-based drug delivery carriers with high safety and efficacy.

SUBMITTER: Lee BR

PROVIDER: S-EPMC6097151 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Nonimmunogenetic Viral Capsid Carrier with Cancer Targeting Activity.

Lee Bo-Ram BR Jo Eunji E Yoon Hong Yeol HY Yoon Chul Joo CJ Lee Hyo-Jung HJ Kwon Koo Chul KC Kim Tae Woo TW Lee Jeewon J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20180627 8

Although protein nanoparticles (PNPs) (e.g., viral capsids) capable of delivering a broad range of drug agents have shown distinctive advantages over synthetic nanomaterials, PNPs have an intrinsic drawback that hampers their clinical application, that is, potential immunogenicity. Here, a novel method for resolving the immunogenicity problem of PNPs, which is based on the genetic presentation of albumin-binding peptides (ABPs) on the surface of PNP, is reported. ABPs are inserted into the surfa ...[more]

PMID: 30128257

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Project description:Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 A resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 A (ref. 2). A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and beta-sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol(-1) of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic maturation process probably present in many dsDNA bacteriophage and possibly viruses such as herpesvirus, which share the HK97 subunit fold.

Dataset Information

Nonimmunogenetic Viral Capsid Carrier with Cancer Targeting Activity.

Publications

Nonimmunogenetic Viral Capsid Carrier with Cancer Targeting Activity.

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