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Chimeric molecules and uses thereof

A chimeric polypeptide and fusion protein technology, applied in the field of treatment or prevention of enveloped virus infection, heterologous structure stabilization part oligomerization of heterologous target molecules, chimeric polypeptide complex

Active Publication Date: 2019-11-26
THE UNIV OF QUEENSLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, traditional protocols for recombinant expression of these proteins generally result in premature triggering and conformational transitions to the structurally more stable postfusion forms

Method used

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  • Chimeric molecules and uses thereof
  • Chimeric molecules and uses thereof
  • Chimeric molecules and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0638] As an example of the ability of the invention to generate chimeric polypeptides comprising the extracellular domain of a viral fusion protein constrained in a prefusion conformation, representative evidence for respiratory syncytial virus fusion proteins is presented.

[0639] Materials and methods

[0640] Chimeric peptide design:

[0641] The extracellular domain of RSV F and RSV-F extracellular domain mutations containing mutations at four sites (S155C, S290C, S190F, and V207L) according to McLellan et al. (Science, 2013.342(6158):592-8) Each body (RSV F dscav) is operatively linked to a downstream heterologous structural stabilizing moiety (SSM) comprising a pair of complementary heptad repeat regions derived from HIV-1 GP160. A control ectodomain construct lacking this SSM and a positive control construct (RSV F ds cav fold) comprising RSV F ds cav operably linked to a folded SSM (foldon SSM) were also generated. The amino acid sequence of the associated protei...

Embodiment 2

[0657] As another example of the ability of the present invention to generate chimeric polypeptides comprising the extracellular domain of a viral fusion protein constrained in a prefusion conformation, the Influenza A virus (INFA) hemagglutinin (HA) protein is provided representative evidence. In addition, representative evidence was provided for the INFA HA protein that a chimeric protein constrained in a prefusion conformation by means of the aforementioned methods was able to induce an improved neutralizing immune response when administered to mice.

[0658] Materials and methods

[0659] Chimeric peptide design:

[0660] The extracellular domain of INFA HA is operably linked to a downstream heterologous structural stabilizing portion comprising a pair of complementary heptad repeat regions derived from HIV-1 GP160. The amino acid sequences of the resulting chimeric proteins and their controls are presented below.

[0661] Extracellular domain of INFA HA (1-529):

...

Embodiment 3

[0677] As yet another example of the ability of the invention to generate chimeric polypeptides comprising the extracellular domain of a viral fusion protein constrained in a prefusion conformation, representative evidence for the Spike protein of the Middle East respiratory syndrome (MERS) virus is provided .

[0678] Materials and methods

[0679] Chimeric peptide design:

[0680] The extracellular domain of the MERS spike protein is operatively linked to a downstream heterologous structural stabilizing portion comprising a pair of complementary heptad repeat regions derived from HIV-1 GP160. The amino acid sequence of the resulting chimeric protein is presented below.

[0681] Extracellular domain of the MERS spike protein (1-1296) – HIV GP160-based SSM:

[0682]MIHSVFLLMFLLTPTESYVDVGPDSVKSACIEVDIQQTFFDKTWPRPIDVSKADGIIYPQGRTYSNITITYQGLFPYQGDHGDMYVYSAGHATGTTPQKLFVANYSQDVKQFANGFVVRIGAAANSTGTVIISPSTSATIRKIYPAFMLGSSVGNFSDGKMGRFFNHTLVLLPDGCGTLLRAFYCILEPRSGNHCPAGNSYTSFATYH...

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Abstract

The present invention discloses chimeric polypeptides based on viral membrane fusion proteins. More particularly, the present invention discloses chimeric polypeptides that comprise a virion surface exposed portion of a viral fusion protein and a heterologous structure- stabilizing moiety, and to complexes of those chimeric polypeptides. The present invention also discloses the use of these complexes in compositions and methods for eliciting an immune response to a fusion protein of an enveloped virus, or complex of the fusion protein, and / or for treating or preventing an enveloped virus infection. The present invention further discloses the use of the heterologous structure-stabilizing moiety for oligomerizing heterologous molecules of interest.

Description

technical field [0001] This application claims priority to Australian Provisional Application No. 2017901152 entitled "Chimeric Molecules and Uses Thereof", filed 30 March 2017, the contents of which are incorporated herein by reference in their entirety. [0002] The present invention generally relates to chimeric polypeptides based on viral membrane fusion proteins. More particularly, the present invention relates to chimeric polypeptides comprising a virion surface-exposed portion of a viral fusion protein and a heterologous structurally stabilizing portion, complexes involving these chimeric polypeptides. The invention also relates to the use of these complexes in compositions and methods for eliciting an immune response against enveloped virus fusion proteins or fusion protein complexes and / or for treating or preventing enveloped virus infections. The invention further relates to the use of a heterologous structure stabilizing moiety to oligomerize a heterologous molecul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C07K14/11C07K14/115C07K14/15C07K14/165C07K14/08A61P31/14
CPCC07K19/00A61P31/14C07K14/005C07K2319/35C12N2740/16122C12N2760/14122C12N2760/14134C12N2760/16122C12N2760/16134C12N2770/10022C12N2770/10034C12N2770/20022C12N2770/20034C07K16/10C07K16/1018C07K16/1045C07K14/16C07K2317/55C12N15/1034C12N2740/16134C12N2760/10022C12N2760/10034C12N2760/14022C12N2760/14034C12N2760/18022C12N2760/18034
Inventor K·J·沙佩尔D·沃特森P·R·杨
Owner THE UNIV OF QUEENSLAND
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