Dataset Information

Peptidic inhibitors for in vitro pentamer formation of human papillomavirus capsid protein l1.

ABSTRACT: A new 14 peptide, originating essentially from the helix 5 of HPV 16L1, illustrates an IC50 of 19.38 nM for the inhibition of HPV 16 L1 pentamer formation, which is highly efficient for targeting a specific protein segment. In addition, mechanism studies reveal that the length, sequence, and the folding of the peptide are critical factors for its inhibition. Particularly, the peptide shows similar inhibition against the pentamer formation of HPV 58L1, although it is designed specially for HPV 16 L1. This study opens a way for the development of high-efficiency, broad-spectrum inhibitors as a new class of anti-HPV agents, which could be extended to the treatment of other virus types.

SUBMITTER: Fu DY

PROVIDER: S-EPMC4394338 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Peptidic inhibitors for in vitro pentamer formation of human papillomavirus capsid protein l1.

Fu Ding-Yi DY Jin Shi S Zheng Dong-Dong DD Zha Xiao X Wu Yuqing Y

ACS medicinal chemistry letters 20150225 4

A new 14 peptide, originating essentially from the helix 5 of HPV 16L1, illustrates an IC50 of 19.38 nM for the inhibition of HPV 16 L1 pentamer formation, which is highly efficient for targeting a specific protein segment. In addition, mechanism studies reveal that the length, sequence, and the folding of the peptide are critical factors for its inhibition. Particularly, the peptide shows similar inhibition against the pentamer formation of HPV 58L1, although it is designed specially for HPV 16 ...[more]

PMID: 25893037

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Project description:Papillomaviruses are a family of nonenveloped DNA viruses that infect the skin or mucosa of their vertebrate hosts. The viral life cycle is closely tied to the differentiation of infected keratinocytes. Papillomavirus virions are released into the environment through a process known as desquamation, in which keratinocytes lose structural integrity prior to being shed from the surface of the skin. During this process, virions are exposed to an increasingly oxidative environment, leading to their stabilization through the formation of disulfide cross-links between neighboring molecules of the major capsid protein, L1. We used time-lapse cryo-electron microscopy and image analysis to study the maturation of HPV16 capsids assembled in mammalian cells and exposed to an oxidizing environment after cell lysis. Initially, the virion is a loosely connected procapsid that, under in vitro conditions, condenses over several hours into the more familiar 60-nm-diameter papillomavirus capsid. In this process, the procapsid shrinks by ~5% in diameter, its pentameric capsomers change in structure (most markedly in the axial region), and the interaction surfaces between adjacent capsomers are consolidated. A C175S mutant that cannot achieve normal inter-L1 disulfide cross-links shows maturation-related shrinkage but does not achieve the fully condensed 60-nm form. Pseudoatomic modeling based on a 9-Å resolution reconstruction of fully mature capsids revealed C-terminal disulfide-stabilized "suspended bridges" that form intercapsomeric cross-links. The data suggest a model in which procapsids exist in a range of dynamic intermediates that can be locked into increasingly mature configurations by disulfide cross-linking, possibly through a Brownian ratchet mechanism. Importance: Human papillomaviruses (HPVs) cause nearly all cases of cervical cancer, a major fraction of cancers of the penis, vagina/vulva, anus, and tonsils, and genital and nongenital warts. HPV types associated with a high risk of cancer, such as HPV16, are generally transmitted via sexual contact. The nonenveloped virion of HPVs shows a high degree of stability, allowing the virus to persist in an infectious form in environmental fomites. In this study, we used cryo-electron microscopy to elucidate the structure of the HPV16 capsid at different stages of maturation. The fully mature capsid adopts a rigid, highly regular structure stabilized by intermolecular disulfide bonds. The availability of a pseudoatomic model of the fully mature HPV16 virion should help guide understanding of antibody responses elicited by HPV capsid-based vaccines.

Dataset Information

Peptidic inhibitors for in vitro pentamer formation of human papillomavirus capsid protein l1.

Publications

Peptidic inhibitors for in vitro pentamer formation of human papillomavirus capsid protein l1.

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