Peptide bicycles with covalent organic cores as research reagents and pharmaceutical drugs

Lead Research Organisation: MRC Laboratory of Molecular Biology

Abstract

We are trying to develop the methods to make a new class of drugs. Most drugs are small molecules that are made by chemistry and are taken by mouth; others, like antibodies, are proteins (large folded polypeptides) that are made by biological methods and are injected. There are many systematic advantages and disadvantages of these two classes of drugs; in particular it is much easier to make antibodies than small molecule drugs, as biological methods (accelerated evolution) are much faster than chemical methods. However the polypeptides are easily digested (which is why they have to be injected); and they do not easily leave the blood stream or enter cells. We are trying to combine the advantages of these two classes of drugs by using simple chemistry with accelerated evolution, and have already produced small indigestible polypeptides against some pharmaceutical targets. However the work is still at an early stage; we do not yet know whether we can combine all the advantages of small molecules and antibodies. Nevertheless a combination of only some of the advantages could prove sufficient to make valuable drugs that are very difficult to make by existing methods; for example, drugs that enter cancer cells and precisely block the targets active in the cancer process.

Technical Summary

Peptide libraries are a rich source of molecular diversity and potentially of powerful drugs. However, peptide drugs suffer from a number of systemic shortcomings inherent in peptide structure and chemistry. These include poor affinity for target due to conformational flexibility, poor serum stability and low bioavailability. Macrocycles are a class of powerful natural drugs and toxins derived from peptide backbones. Their structures reveal strategies (such as cyclization, chemical modification and cross-linking) that address the shortcomings of peptide drugs. However, in nature, macrocycles are produced through dedicated non-ribosomal synthesis pathways, which, so far, have proved refractory to engineering or evolution to produce tailor-made compounds. This research program is aimed at the synthesis and evolution of peptide macrocycles with therapeutic potential using ribosomal peptide synthesis and harnessing both natural and chemical combinatorial diversity for directed evolution of novel peptide macrocycles. In particular, the program is aimed at the phage display of diverse peptide libraries comprising a defined number of chemical functionalities that allow peptide cyclization and folding around one or multiple organic cores. By tethering discrete peptide loops to a chemical and rigid scaffold this strategy not only constrains conformational flexibility, and greatly reduces susceptibility to proteolytic degradation, but also extends the chemical diversity of peptides by virtue of the organic core, which may include a wide variety of functionalities not present in nature. Chemical diversity may be further expanded through the incorporation of unnatural amino acids in the peptide loops, specific chemical modification of side-chains and / or N- or C-termini. In combination with the power of repertoire selection, this approach promises to deliver tailor-made designer ligands of low molecular weight, defined compact structure and high serum stability with obvious potential as a novel class of bio-therapeutics.

Publications

10 25 50
 
Description Jeantet Fellowship - Bernard
Amount £117,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 05/2013
 
Description Jeantet Fellowship - Jaworski
Amount £35,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 08/2009 
End 07/2010
 
Description Jeantet Fellowship - Teufel
Amount £25,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 08/2009 
End 02/2010
 
Title Phage display of bicyclic peptides 
Description A method was developed for making bicyclic peptides with a covalent chemical core that can be regarded as small antibody mimics 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Founding of spin out company Bicycle Therapeutics 
 
Description Developing therapies from bicyclic peptides 
Organisation Bicycle Therapeutics
Country United Kingdom 
Sector Private 
PI Contribution Provision of benchspace and access to equipment and comsumables to researcher; scientific guidance
Collaborator Contribution Scientific researcher from Bicycle Therapeutics hosted by LMB to help develop technology
Impact Patent Licensing agreement
Start Year 2009
 
Description EPFL Partnership 
Organisation Swiss Federal Institute of Technology in Lausanne (EPFL)
Country Switzerland 
Sector Public 
PI Contribution My research team is working jointly with EPFL on the development of bicycles.
Collaborator Contribution Prof Christian Heinis was scientific founder of Bicycles Therapeutics together with Greg Winter. Prof Heinis provided scientific advice and guidance.
Impact Licensing agreement
Start Year 2010
 
Title Methods and compositions 
Description Small antibody mimics that binding to therapeutic targets can be created by building bicyclic peptides on a chemical core 
IP Reference WO2009098450 
Protection Patent granted
Year Protection Granted 2009
Licensed Yes
Impact Formation of a spin out company Bicycle Therapeutics
 
Title Multispecific Peptides 
Description The invention relates to a method for providing a multispecific peptide ligand comprising a polypeptide covalently linked to a molecular scaffold at three or more amino acid residues and capable of binding to two or more separate targets, comprising the steps of; (a) providing a first repertoire of polypeptides, each polypeptide comprising two or more reactive groups capable of covalent linkage to a molecular scaffold, and at least one loop which comprises a sequence of two or more amino acids subtended between two of said reactive groups; (b) providing a second repertoire of polypeptides as described in (a); (c) joining at least one loop of one or more members of the first repertoire to at least one loop of one or more members of the second repertoire to form at least one polypeptide comprising two loops, and (d) conjugating the composite polypeptide(s) to a molecular scaffold at at least three amino acid positions 
IP Reference WO2010089115 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Consolidation of IP state of Bicycle Therapeutics
 
Title Peptide Libraries 
Description The invention relates to a method for altering the conformational diversity of a first repertoire of polypeptide ligands, comprising a plurality of polypeptides comprising at least two reactive groups separated by a loop sequence covalently linked to a molecular scaffold which forms covalent bonds with said reactive groups, to produce a second repertoire of polypeptide ligands, comprising assembling said second repertoire from the polypeptides and structural scaffold of said first repertoire, incorporating one of the following alterations: (a) altering at least one reactive group; or (b) altering the nature of the molecular scaffold; or (c) altering the bond between at least one reactive group and the molecular scaffold; or (d) any combination of (a), (b) or (c). 
IP Reference WO2011018227 
Protection Patent granted
Year Protection Granted 2011
Licensed Yes
Impact Consolidation of IP state of Bicycle Therapeutics
 
Title Structured Peptide Processing 
Description The invention relates to a method for modifying one or more peptide ligands, comprising polypeptides covalently linked to a molecular scaffold at two or more amino acid residues, comprising the steps of providing one or more peptide ligands, wherein the polypeptide comprises two or more reactive groups which form a covalent linkage to the molecular scaffold, and at least one loop which comprises a sequence of two or more amino acids subtended between two of said reactive groups; exposing the peptide ligands to one or more proteases; and sorting the ligands according to the extent of proteolytic cleavage. 
IP Reference WO2010089116 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Consolidation of IP Estate of Bicycle Therapeutics
 
Title Structured Polycyclic Peptide 
Description The invention relates to a peptide ligand comprising a polypeptide linked to a molecular scaffold at n attachment points, wherein said polypeptide is cyclised and forms n separate loops subtended between said n attachment points on the molecular scaffold, wherein n is greater than or equal to 2. 
IP Reference WO2010089117 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Consolidation of IP estate of Bicycle Therapeutics
 
Company Name Bicycle Therapeutics 
Description Bicycle Therapeutics is a biotechnology company developing a platform technology that enables the creation of a new generation of biotherapeutics which combine the desirable features of small molecules and biopharmaceuticals to create highly specific and highly stable drugs. http://www.bicycletherapeutics.com/ 
Year Established 2009 
Impact Bicycles Therapeutics has entered into a collaboration and license agreement with ThromboG enics NV to develop potent and selective bicyclic peptide inhibitors against a specific drug target of interest for the treatment of ophthalmic diseases, such as diabetic macular edema (DME)
Website http://www.bicycletherapeutics.com/
 
Description Australian media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by ABC Radio and TV for programs on my work on antibody therapeutics

Not known
Year(s) Of Engagement Activity 2008
 
Description Japanese industrialists-Tokyo 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Described antibody technologies to Japanese industrialists at British Embassy Tokyo

None yet
Year(s) Of Engagement Activity 2007,2008,2009