The Nobel Committees have recently announced the much-anticipated Nobel Prize winners of 2022, honouring the contributions that, as per Alfred Nobel’s will of 1895, “have conferred the greatest benefit to humankind”. In this series of articles, we present selected patents of these winners, that, at least to some extent, result from or lead to their celebrated works. For those with an interest in the most commemorated scientific and technological achievements in 2022 and intellectual property, this series makes for interesting reading.
On 5 October 2022, the Royal Swedish Academy of Sciences announced that the 2022 Nobel Prize in chemistry was rewarded to Carolyn R. Bertozzi, Morten Meldal and K. Barry Sharpless “for the development of click chemistry and bioorthogonal chemistry”.
The Committee commended that:
Barry Sharpless – who is now being awarded his second Nobel Prize in Chemistry – started the ball rolling. Around the year 2000, he coined the concept of click chemistry, which is a form of simple and reliable chemistry, where reactions occur quickly and unwanted by-products are avoided.
Shortly afterwards, Morten Meldal and Barry Sharpless – independently of each other – presented what is now the crown jewel of click chemistry: the copper catalysed azide-alkyne cycloaddition. This is an elegant and efficient chemical reaction that is now in widespread use. Among many other uses, it is utilised in the development of pharmaceuticals, for mapping DNA and creating materials that are more fit for purpose.
Carolyn Bertozzi took click chemistry to a new level. To map important but elusive biomolecules on the surface of cells – glycans – she developed click reactions that work inside living organisms. Her bioorthogonal reactions take place without disrupting the normal chemistry of the cell.
We present herein three patent families with each one of the winners listed as one of the inventors. These families relate to products or methods that are derived from, inspired by or can be applied with click chemistry.
Barry Sharpless – Copper-catalysed ligation of azides and acetylenes
This family of patents claims priority from US60/385041 and has a priority date of 30 May 2002. AU2003240482, for example, has seven independent claims. The first four are directed to a process of preparing a 1,4-disubstituted 1,2,3-triazole with a first reactant having a terminal alkyne moiety and second reactant having an azide moiety for forming a 1,4-disubstituted 1,2,3-triazole, wherein the click chemistry ligation reaction is performed at various conditions. For example, independent claim 1 recites:
1. A process of preparing a 1,4-disubstituted 1,2,3-triazole between a first reactant having a terminal alkyne moiety and second reactant having an azide moiety for forming a 1,4-disubstituted 1,2,3-triazol, the click chemistry ligation reaction being catalyzed by an addition of Cu (II) in the presence of a reducing agent for reducing said Cu(II) to Cu(I), in situ, said Cu(I) being present in catalytic amount.
The latter three independent claims are directed to processes of producing 1,4-disubstituted 1,2,3-triazole derivative or polyvalent 1,4-disubstituted 1,2,3-triazole. For example, independent claim 13 recites:
13. A one step process for producing a polyvalent 1,4-disubstituted 1,2,3-triazole, the process comprising the step: derivatizing a polyalkyne core by addition of an azide containing molecule in the presence of a catalytic amount of Cu(I)
This family of patents discloses a method for producing 1,4-disubstituted 1,2,3-triazoles, found to be important in various aspects e.g. in pharmaceutical chemistry, using click chemistry ligation with a copper-ion based catalyst.
Carolyn Bertozzi – Compositions and methods for modification of biomolecules
This family of patents claims priority from US60/624202 and has a priority date of 1 November 2004. It discloses modified cycloalkyne compounds and method of use of such compounds in modifying biomolecules. Importantly, it discloses a cycloaddition reaction that can be carried out under physiological conditions. The process avoids the use of copper-based catalysts, since copper is toxic to both bacterial and mammalian cells. US10434111, for example, recites a method for modification of a target molecule comprising an azide in claim 1:
1. A method for chemoselective modification of a target molecule comprising an azide, the method comprising:
reacting an azide of a target molecule with a modified cycloalkyne of the formula:
X is a cyclooctyne group or a heterocyclooctyne group, substituted with R1, and optionally substituted with one or more additional groups;
R1 is selected from a carboxylic acid, an alkyl ester, an aryl ester, a substituted aryl ester, an aldehyde, an amide, an aryl amide, an alkyl halide, a thioester, a sulfonyl ester, an alkyl ketone, an aryl ketone, a substituted aryl ketone, a halosulfonyl, a nitrile, and a nitro; and
Y is a linked moiety that comprises a reactive group that facilitates covalent attachment of a molecule of interest, or a molecule of interest,
wherein said reacting produces a conjugate between the azide of the target molecule and the modified cycloalkyne.
The modified cycloalkyne compounds are useful in research e.g. in exploring functional and physical characteristics of a receptor; proteomics; metabolomics; and the like. They may also be used in diagnostic applications e.g., for detection of cancer; and the like, where a modified cycloalkyne comprising a detectable label is used to label an azide-modified target molecule. A further use is in therapy, where a drug is delivered to an azide-modified target molecule using a modified cycloalkyne covalently linked to a drug.
Morten Meldal – Binding peptides
This family of patents claims priority from Danish application No. PA201670899 and has a priority date of 11 November 2016. WO2018087232, for example, discloses a β body comprising at least two β-strand peptide sequences connected by β-turn peptide sequence(s), wherein said β-strand peptide sequences are organized in an anti-parallel arrangement of alternating forward and reverse β-strand peptide sequences. Each forward β-strand peptide sequence individually has the sequence of Xr(ZX)m, and each reverse β-strand peptide sequence individually has the sequence of (XZ)nXr.
In one embodiment, the Z moiety is one or more strand bridging amino acids. Preferably, the amino acids substituted with either alkyne or azide, which are useful for click chemistry. A cyclization through click formation of a triazole or a disulfide bond may be undertaken to increase β-structure stability and selectivity. Alternatively, where the β-body is to be linked to a conjugated moiety the β-body may be equipped with an extra amino acid building block containing a suitable click partner. Upon purification it may be attached to a biocompatible resin or another surface using click chemistry.
The patents and works of Carolyn R. Bertozzi, Morten Meldal and K. Barry Sharpless are well worth a more detailed review for interested parties.