Surface-functionalized optical element

Abstract

The present invention is directed to a surface-functionalized optical element comprising an IR-transmissive optical element, wherein at least a part of the surface of the IR-transmissive optical element is covalently bonded to a molecular probe by a linker construct. The linker construct comprises a surface attachment moiety and a spacer moiety comprising poly(alkylene oxide). The present invention further relates to a process for preparing the surface-functionalized optical element, an optical biosensor comprising the surface-functionalized optical element, and a method for detecting a target analyte using the surface-functionalized optical element.

Description

【Technical Field】 【0001】 The present invention relates to the field of surface-functionalized optical elements such as surface-functionalized ATR-IR waveguides, and optical biosensors including such surface-functionalized optical elements. The surface-functionalized optical elements and biosensors including the same can be used in methods for detecting target analytes, among other things. 【Background Art】 【0002】 Surface-functionalized optical elements are widely used in biosensing applications or biosensors. In such applications, molecular probes are immobilized on the surface of the optical element. The immobilized molecular probes can specifically bind to target analytes. The chemical / (biochemical) interaction between the molecular probe and the target analyte produces a measurable signal specific to each target analyte. The measured signal is due to a physicochemical change that can be measured by optical spectroscopy via an optical element serving as a so-called transducer element. 【0003】 For example, International Publication No. 2015 / 121339 describes an infrared sensor element for directly analyzing the quantity and secondary structure of a candidate biomarker protein that has undergone a conformational conversion related to disease progression. The infrared sensor element includes a germanium internal reflection element and at least one receptor for the biomarker protein, and the biomarker protein is an antibody capable of specific and conformationally independent binding to the candidate biomarker protein, and is directly grafted onto at least one surface of the germanium internal reflection element by silanization with a short silane linker or thiolation with a short thiol linker, reacting the freely accessible amine group of the at least one receptor with an amine-reactive group on the short silane / thiol linker, and an antibody capable of blocking the remaining amine-reactive groups on the short silane / thiol linker with a blocking substance that does not cross-react with the candidate biomarker protein. 【0004】 In known surface-functionalized optical elements, the functional groups and / or molecular probes may be insufficiently immobilized on the surface of the optical element. Insufficient immobilization can cause direct or delayed detachment of the functional groups and / or molecular probes from the optical element on the surface, for example, during cleaning or measurement steps under a continuous flow of solvent across the functionalized surface. As a result, it is possible to reduce the lifespan and functionality of the functionalized surface. SUMMARY OF THE INVENTION 【0005】 There continues to be a need in the art to provide surface-functionalized optical elements that are stable and / or exhibit a reduction in the detachment of functional groups from the surface. 【0006】 In one aspect of the present invention, a surface-functionalized optical element is provided. The surface-functionalized optical element includes an IR-transmissive optical element, and at least a portion of the surface of the IR-transmissive optical element is bonded to a molecular probe by a linker construct, wherein the linker construct includes a surface attachment portion, and a spacer portion including poly(alkylene oxide). 【0007】 The inventors have surprisingly found that by binding molecular probes to the surface of an optical element with a specific linker construct as defined herein, the stability of the surface-functionalized optical element is improved. For example, functional groups bound to the surface are less likely to be removed from the optical element than in the case of equivalent surface-functionalized optical elements using different linkers to bind the molecular probes to the surface. Thereby, the functionality and lifespan of the surface-functionalized optical element of the present invention are improved. 【0008】 In another aspect of the present invention, an optical biosensor is provided that includes a surface-functionalized optical element as defined herein. 【0009】 ​In another aspect of the present invention, a process for preparing a surface-functionalized optical element as defined herein is provided. The process comprises (a) providing an IR-transmissive optical element, (b) reacting at least a portion of the surface of the IR-transmissive optical element with a compound containing poly(alkylene oxide) (PAO) and includes. 【0010】 In another aspect of the present invention, a method for detecting a biomarker is provided. The method comprises (i) contacting a surface-functionalized optical element as defined herein with a suspect sample containing a target analyte, optionally the sample is a human body fluid; (ii) detecting a biomarker based on the interaction between the molecular probe and the target analyte, optionally the interaction between the molecular probe and the target analyte is detected by infrared spectroscopy, and optionally the biomarker is based on the band position of amide I of the target analyte and includes. 【0011】 In yet another aspect of the present invention, companion diagnostic tests, diagnosing a protein misfolding disease, diabetes or a tumor in a patient, monitoring the therapy of a patient having a protein misfolding disease, diabetes or a tumor, and screening for drugs for the treatment of a protein misfolding disease, diabetes or a tumor the use of a surface-functionalized optical element as defined herein or an optical biosensor as defined herein for one or more of 【0012】 When the term "comprising" is used in the description and claims of the present invention, it does not exclude other unspecified elements having primary or minor functional importance. For the purposes of the present invention, the terms "consisting essentially of" and "consisting of" are considered specific embodiments of the term "comprising". Henceforth, when a group is defined as including at least a certain number of features or embodiments, it is also understood, optionally, to disclose a group consisting essentially of or consisting of only these features or embodiments. 【0013】 Whenever the terms "including" or "having" are used, they are meant to be equivalent to "comprising" as defined above. When indefinite or definite articles such as "a", "an", or "the" are used to refer to a singular noun, it includes the plural form of that noun unless otherwise specified. The term "obtained" does not mean that an embodiment must be obtained by a series of steps following, for example, the term "obtained", even if such a limited understanding is always included as a preferred embodiment by the term "obtained". 【DETAILED DESCRIPTION OF THE INVENTION】 【0014】 Surface-functionalized optical element In one aspect of the present invention, a surface-functionalized optical element is provided. The surface-functionalized optical element is an IR-transmissive optical element comprising at least a part of the surface of the IR-transmissive optical element being bonded to a molecular probe by a linker construct, wherein the linker construct comprises a surface attachment moiety, and a spacer moiety comprising a poly(alkylene oxide). comprises. 【0015】 The surface-functionalized optical element may include additional elements, such as a matrix silane or one or more incomplete linker constructs as defined herein. An "incomplete linker construct" is understood to be a by-product that binds to the surface during the preparation of the surface-functionalized optical element but does not contain all parts of the linker construct (e.g., its reactive functionality has been quenched during the preparation) or does not bind to the molecular probe. 【0016】 According to one embodiment, the surface-functionalized optical element is an IR-transmissive optical element, at least a part of the surface of the IR-transmissive optical element as defined herein is bound to a molecular probe by a linker construct, and optionally at least a part of the surface of the IR-transmissive optical element is covalently bonded to a matrix silane as defined herein. According to one embodiment, the surface-functionalized optical element is an IR-transmissive optical element, at least a part of the surface of the IR-transmissive optical element as defined herein is bound to a molecular probe by a linker construct, at least a part of the surface of the IR-transmissive optical element is covalently bonded to a matrix silane as defined herein, and optionally at least a part of the surface of the IR-transmissive optical element is bound to an incomplete linker construct. 【0017】 IR-transmissive optical element The surface-functionalized optical element includes an IR-transmissive optical element. 【0018】 The IR-transmissive optical element may be any optical element suitable for binding an organic linker compound to its surface. 【0019】 The IR-transmissive optical element may be an optical element suitable for use in an optical biosensor. According to one embodiment, the IR-transmissive optical element is an IR-transmissive optical element suitable for attenuated total reflection (ATR) spectroscopy, transmission spectroscopy, or surface-enhanced infrared absorption (SEIRA) spectroscopy. According to one preferred embodiment, the IR-transmissive optical element is suitable for attenuated total reflection infrared (ATR-IR) spectroscopy or transmission infrared spectroscopy. 【0020】 The IR-transmissive optical element preferably has a wavenumber range of 40 to 13,000 cm -1 more preferably 500 to 4,000 cm -1 even more preferably 900 to 4,000 cm -1 for example, 1,400 to 1,800 cm -1 or 1,500 to 1,750 cm -1 and is at least transmissive to infrared radiation at these wavenumber ranges. 【0021】 According to one preferred embodiment, the IR-transmissive optical element is an IR-transmissive optical waveguide, such as an ATR-IR waveguide. According to one preferred embodiment, the IR-transmissive optical element is an ATR-IR waveguide. 【0022】 According to one embodiment, the IR-transmissive optical element is a material and / or crystal selected from the group consisting of plastic, glass, diamond, germanium, silicon, silicon dioxide, silver halide, GaAs, ZnSe, ZnS, thallium(I) mixed halide (e.g., KRS-5), and AMTIR. "AMTIR" is an amorphous material that transmits infrared radiation and is known in the art. A suitable AMTIR can be Ge 33 As 12 Se 55 (AMTIR-1). 【0023】 According to one preferred embodiment, the IR-transmissive optical element is an ATR-IR waveguide made of silicon crystal or germanium crystal, more preferably an ATR-IR waveguide made of silicon crystal. 【0024】 The surface of the IR-transmissive optical element may be at least partially modified, for example, at least partially modified by an oxide layer (e.g., a silicon dioxide layer). The surface modification can further assist in the attachment of a linker construct, for example, a linker construct containing a surface attachment moiety that covalently binds to the optical element via a silane group. 【0025】 Thus, in one embodiment of the present invention, at least a part of the IR-transmissive optical element has an oxide surface layer, and at least a part of the oxide surface layer is covalently bonded to a linker construct. The oxide surface layer is preferably a metal oxide surface layer or a metalloid oxide surface layer. A "metalloid oxide" is an oxide of an element selected from the group consisting of boron, silicon, germanium, arsenic, antimony, and tellurium. 【0026】 More preferably, the metal oxide surface layer or the metalloid oxide surface layer is a silicon dioxide surface layer. 【0027】 According to one embodiment, at least a part of the IR-transmissive optical element has an oxide surface layer, preferably a silicon dioxide surface layer, and at least a part of the oxide surface layer is covalently bonded to a silane group of the surface-attached portion of the linker construct. 【0028】 According to one preferred embodiment, the IR-transmissive optical element is an attenuated total reflection infrared (ATR-IR) waveguide, at least a part of the IR-transmissive optical element has an oxide surface layer, and at least a part of the oxide surface layer is covalently bonded to a linker construct. 【0029】 According to one preferred embodiment, the IR-transmissive optical element is a silicon crystal or a germanium crystal, the silicon crystal or the germanium crystal has an oxide surface layer, preferably a silicon dioxide surface layer, and at least a part of the oxide surface layer is covalently bonded to a linker construct. 【0030】 Linker construct The surface-functionalized optical element includes a linker construct. At least a part of the surface of the IR-transmissive optical element is bound to a molecular probe by the linker construct. The surface of the IR-transmissive optical element can be covalently bonded to a molecular probe by the linker construct. Thus, according to one embodiment, the linker construct covalently bonds a molecular probe to the surface of the IR-transmissive optical element. 【0031】 "Covalently attached" in the context of the disclosure of the present invention can be understood to mean that the linker construct includes at least one continuous chain of sigma bonds that connects the surface of the IR transmissive optical element to the molecular probe. 【0032】 According to one embodiment, the linker construct does not contain a coordination transition metal complex, a protein-ligand complex, and a protein-protein complex. The coordination transition metal complex can be, but is not limited to, a histidine nickel complex. The protein-ligand complex can be, but is not limited to, a biotin-avidin or biotin-streptavidin complex. The protein-protein complex can be, but is not limited to, an antibody-antigen complex. 【0033】 Surface attachment moiety The linker construct includes a surface attachment moiety. The surface attachment moiety covalently attaches the linker construct to the optical element. The surface attachment moiety is not particularly limited as long as the moiety is suitable for attaching the linker construct to the surface of the optical element. 【0034】 According to one embodiment, the surface attachment moiety includes a silane group or a sulfide group, preferably a silane group. 【0035】 For example, the silane group can be used to attach the surface attachment moiety to an IR transmissive optical element (such as a silicon optical element) having an oxide surface layer, such as a metalloid oxide surface layer (such as silicon dioxide). 【0036】 The sulfide group can be used to attach the surface attachment group to a germanium optical element and / or an IR transmissive optical element that is a germanium crystal. 【0037】 The silane group may have the formula: / / -O-Si(R 1 )2-A and, wherein R 1are each independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si x selected from x and Si / / represents attachment to the surface of the IR transmitting optical element, A represents attachment to the remaining linker construct. 【0038】 According to one embodiment, the surface attachment moiety has the formula (S-I): / / -Y 1 -L 1 -X 1 -$$ 1 (S-I) having a structure according to wherein / / represents attachment to the surface of the IR transmitting optical element, Y 1 is -O-Si(R 1 )2-, and R 1 are each independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si x selected from x and Si L 1 is an optional linking unit, X 1 is a group selected from -C(O)NH-, -NHC(O)-, -NHC(O)HN-, and -NHC(O)O-, $$ 1 represents attachment to the spacer moiety. 【0039】 According to one preferred embodiment, the surface attachment moiety has the formula (S-I): / / -Y 1-L 1 -X 1 -$$ 1 (S-I) has a structure according to, wherein, / / represents adhesion to the surface of the IR transmissive optical element, Y 1 is -O-Si(R 1 )2-, and R 1 are each independently H, OH, alkyl which may optionally be substituted, alkoxy which may optionally be substituted, -O- / / , and -O-Si x selected from, and Si x is a silicon atom of a surface-attached moiety containing another silicon or a silicon atom of a matrix silane attached to the surface of an optional IR transmissive optical element, and optionally R 1 are each independently selected from C1-C6-alkoxy, -O- / / , and -O-Si x selected from, and Si x is a silicon atom of a surface-attached moiety containing another silicon or a silicon atom of a matrix silane attached to the surface of an optional IR transmissive optical element, L 1 is a C1-C12 alkyl group, preferably a C1-C6 alkyl group (e.g., propyl), X 1 is a group selected from -C(O)NH- and -NHC(O)-, preferably -NHC(O)-, $$ 1 represents adhesion to the spacer moiety. 【0040】 According to another embodiment, the surface-attached moiety has the formula (S-II): / / -Y 3 -L 8 -$$ 1 (S-II) has a structure according to, wherein, / / represents adhesion to the surface of the IR transmissive optical element, Y 3is -S- and L 8 is a linking unit, preferably an optionally substituted alkyl group, such as an optionally substituted C1-C12 alkyl group $$ 1 represents attachment to the spacer moiety 【0041】 Spacer moiety Furthermore, the linker construct includes a spacer moiety. The spacer moiety includes a poly(alkylene oxide). 【0042】 The inventors have surprisingly found that the use of a spacer moiety containing a poly(alkylene oxide) improves the stability of the surface-functionalized optical element compared to a linker construct that does not contain a poly(alkylene oxide). Furthermore, the inventors have found that the use of a spacer moiety containing a poly(alkylene oxide) improves the stability of the surface-functionalized optical element compared to a linker construct that does not contain a poly(alkylene oxide). 【0043】 The alkylene subunits of the poly(alkylene oxide) may be optionally substituted. The poly(alkylene oxide) may be, but is not limited to, poly(ethylene oxide), poly(propylene oxide), poly(butylene oxide), or a block copolymer thereof. 【0044】 Preferably, the poly(alkylene oxide) is poly(ethylene oxide), which is also referred to in the art as polyethylene glycol or PEG. According to one preferred embodiment, the poly(alkylene oxide) is a polyethylene glycol having 2 to 100 glycol repeat units, more preferably 2 to 50 repeat units, even more preferably 2 to 25 repeat units, even more preferably 2 to 16 repeat units, such as 3 to 8 glycol repeat units or 3 to 6 glycol repeat units. 【0045】 The spacer part preferably further contains a ligation group. The ligation group binds the molecular probe to the linking unit of the spacer part or to another part of the linker construct. Preferably, the ligation group covalently binds between the poly(alkylene oxide) of the spacer part and the molecular probe. 【0046】 The ligation group is obtained when preparing the linker construct, and specifically can be understood as a structural unit obtained when (i) reacting the precursors of the linker construct with each other, (ii) attaching the molecular probe to the linker construct, or (iii) reacting the precursor of one linker construct with a molecular probe pre-labeled with the precursor of another linker construct. Further details on how the ligation group can be obtained will be described later in connection with the process of the present invention. 【0047】 Depending on the structure of the linker construct and its preparation process, the spacer part may contain one or more ligation groups. 【0048】 The one or more ligation groups may be, but are not limited to, esters, hydrazones, amides, hydrazones, succinimides or ring-opening products of succinimides, or groups obtainable by bioorthogonal ligation reactions. 【0049】 One of ordinary skill in the art understands the bioorthogonal ligation reactions and chemical structures of the groups that may be obtained by the above reactions. Bioorthogonal ligation reactions include, but are not limited to, Staudinger ligation, azide and alkyne, azide and cycloalkyne ("copper-free click reaction"), [2+3]-addition cyclization between nitrone and cycloalkyne ("click reaction"), [2+4]-addition cyclization between tetrazine and trans-alkene ("tetrazine ligation"), oxime / hydrazine formation from aldehydes and ketones, and the like. Therefore, the bioorthogonal ligation reaction is preferably one of the following reactions: (i) the reaction between azide and phosphine or phosphite; (ii) the reaction between azide and alkyne (including cycloalkyne); (iii) the reaction between azide and cycloalkyne; (iv) the reaction between tetrazine and trans-alkene; (v) the reaction that forms oxime and / or hydrazone. 【0050】 In one embodiment, the spacer portion includes a ligation group covalently bonded to the molecular probe. For example, the ligation group may be an ester, hydrazone, amide, succinimide, or an open-ring product of succinimide, and optionally has one of the following structures: 【0051】 【Chemical formula】 wherein Q 1 is the NH, O, or S atom of the molecular probe. When the molecular probe contains an amino acid (for example, when the molecule is an antibody), Q 1 may be the NH, O, or S of the amino acid of the molecular probe. For example, Q 1 may be the NH of the lysine side chain. 【0052】 In one embodiment, the spacer portion comprises a ligation group obtainable by a bioorthogonal ligation reaction. According to one embodiment, the spacer portion optionally comprises an N - heterocyclic group selected from the group consisting of a triazole group, a dihydropyridazine group, a pyridazine group, and an isoxazoline group. 【0053】 According to one preferred embodiment, the spacer portion comprises an N - heterocyclic group selected from the group consisting of a triazole group, a dihydropyridazine group, a pyridazine group, and an isoxazoline group. Preferably, the N - heterocyclic group is a triazole group. Preferably, the N - heterocyclic group covalently bonds between the poly(alkylene oxide) of the spacer portion and the molecular probe. 【0054】 According to one embodiment, the spacer portion has a structure according to any one of formulas (HET - I) to (HET - VI): 【0055】 【Chemical formula】 and comprises an optionally substituted N - heterocyclic group having a structure according to any one of them as a ligation group, wherein, && 1 represents the attachment to the linking unit or poly(alkylene oxide) of the spacer portion, && 2 represents the attachment to the linking unit of the spacer portion, another part of the linker construct or the molecular probe, Ring A is an optionally substituted 8 - membered carbocyclic compound or an optionally substituted 8 - membered heterocycle, preferably an optionally substituted dibenzo - fused 8 - membered N - heterocycle, R * is H, an optionally substituted alkyl group or an optionally substituted aryl group, preferably a C1 - C6 alkyl group (such as methyl); Preferably, the optionally substituted N - heterocyclic group is of formula (HET - II) or (HET - V): 【0056】 [Chemical formula] has a structure according to 【0057】 According to one embodiment, the spacer portion has the formula (SP-II) $$ 2 -L 2 -X 2 -L 3 -H 1 -L 4 -§§ 1 (SP-II) has a structure according to wherein $$ 2 represents attachment to the surface attachment portion, L 2 ~L 4 are each independently an optional linking unit, X 2 is -(OCH2CH2)n 1 -, and n1 is an integer from 2 to 100, preferably from 2 to 50, more preferably from 2 to 25, and even more preferably from 2 to 16 (for example, 3 to 6), H 1 has a structure according to any one of the formulas (HET-I) to (HET-VI): 【0058】 [Chemical formula] is an optionally substituted N-heterocyclic group having a structure according to any one of them, && 1 represents attachment to L 3 or corresponds to X 3 when L 2 is absent, && 2 represents attachment to L 4 or corresponds to §§ 4 when L 1 is absent, R *is H, an optionally substituted alkyl group or an optionally substituted aryl group, preferably a C1-C6 alkyl group (e.g., methyl); Ring A is an optionally substituted 8-membered carbocyclic compound or an optionally substituted 8-membered heterocycle, preferably an optionally substituted dibenzo-fused 8-membered N-heterocycle; §§ 1 represents another part of the linker construct or attachment to a molecular probe, preferably, the optionally substituted N-heterocyclic group is of formula (HET-II) or (HET-V): 【0059】 【Chemical formula】 has a structure according to 【0060】 Peptide moiety The linker construct may optionally include a peptide moiety that covalently links between the spacer moiety and the molecular probe. The peptide moiety functions as a blocking layer or as part of a blocking layer. It is understood and expected that the blocking layer can be formed at least in part by the peptide moieties of a plurality of linker constructs bound to the surface of the IR-transmissive optical element. 【0061】 Surprisingly, the inventors have found that covalently bonding a peptide moiety between the spacer moiety and the molecular probe increases the inertness of the surface-functionalized optical element to non-specific binding. The peptide moiety may function as a blocking moiety or, together with other peptide moieties on the surface, as a blocking layer. Furthermore, it has been found that including a peptide moiety in the linker construct can obviate the need for blocking of conventional surface-functionalized optical elements. The peptide moiety may also function as a synthetic handle or synthetic platform for the control of molecular probe binding. 【0062】 The peptide moiety contains a peptide compound. The "peptide compound" in the sense of the present invention is a compound containing at least two, optionally at least four, amino acids linked by peptide bonds. In this context, "amino acid" is to be broadly understood as a compound containing a carboxylic acid group and an amino group. 【0063】 The peptide compound is preferably selected from the group consisting of peptides, proteins, and protein fragments, each of which may optionally be substituted. The optional substituents may include, but are not limited to, PEG groups. Thus, the peptide compound may be a substituted peptide, such as a pegylated peptide. 【0064】 The peptide compound is preferably a peptide compound that does not have, or essentially does not have, binding affinity for the target analyte of the molecular probe or the fluid containing the target analyte, such as a body fluid (e.g., plasma or CSF). The peptide compound is preferably a peptide compound that is inert to the target analyte of the molecular probe or the fluid containing the target analyte, such as a body fluid (e.g., plasma or CSF). 【0065】 The peptide compound may be a natural, semi-synthetic or synthetic peptide, optionally substituted, having an amino acid chain length of optionally 2 to 600 amino acids, optionally 2 to 400 amino acids, optionally 2 to 200 amino acids, optionally 2 to 100 amino acids. The peptide compound may be a natural, semi-synthetic or synthetic peptide having an amino acid chain length of 2 to 100 amino acids (e.g., 5 to 100 amino acids or 10 to 100 amino acids). Preferably, the peptide compound contains one or more amino acids containing an H2N-, HO- or HS- group, more preferably an H2N- group, such as the H2N- group of a lysine side chain, in its / their side chain. 【0066】 The peptide compound may be a fragment of a protein. The fragment of the protein is available by or obtainable by protein hydrolysis. Accordingly, the peptide compound may be available from or obtained from a protein hydrolysate. For example, the peptide compound may be available from or obtained from a hydrolysate of albumin, casein, BSA, serum protein (e.g., animal serum such as porcine, equine, or caprine serum), milk protein, or a mixture thereof. Preferably, the peptide compound is available from or obtained from a protein hydrolysate, such as a casein hydrolysate. 【0067】 The peptide compound may be an optionally substituted peptide having an amino acid chain length of optionally 2 to 600 amino acids, optionally 2 to 400 amino acids, optionally 2 to 200 amino acids (e.g., 2 to 100, 5 to 100, or 10 to 100), and such a peptide is available from or obtained from a protein hydrolysate. The peptide compound may be an optionally substituted peptide having an amino acid chain length of 2 to 600 amino acids, optionally 2 to 400 amino acids, optionally 2 to 200 amino acids (e.g., 2 to 100, 5 to 100, or 10 to 100), and such a peptide is available from or obtained from a protein hydrolysate, and such a protein is selected from the group consisting of albumin, casein, BSA, serum protein, milk protein, and mixtures thereof. The peptide compound may be an optionally substituted peptide having an amino acid chain length of 2 to 100 amino acids (e.g., 5 to 100 or 10 to 100), and such a peptide is available from or obtained from a casein hydrolysate. The casein hydrolysate may be a hydrolysate of high-purity casein. 【0068】 Structure of the linker construct The linker construct may have different chemical structures depending on the synthetic procedure for attaching the molecular probe to the surface of the IR-transmissive optical element and further depending on the number of parts of the linker construct. 【0069】 The linker construct generally has the formula (A): / / -(S)-(SP)-\\ (A) and can be defined by a structure according to wherein / / represents attachment to the surface of the IR-transmissive optical element, (S) represents the surface attachment part, (SP) represents the spacer part, \\ represents attachment to another part of the linker construct or to the molecular probe. 【0070】 The spacer part (SP) may be directly attached to the molecular probe. Alternatively, the spacer part (SP) may be attached to another part of the linker construct, such as a peptide part defined in relation to a linker structure according to the following formula (B). 【0071】 According to one embodiment, the surface attachment part (S) has a structure according to the formula (S-I): / / -Y 1 -L 1 -X 1 -$$ 1 (S-I) and has a structure according to wherein / / represents attachment to the surface of the IR-transmissive optical element, Y 1 is -O-Si(R 1 )2-, and R 1 are each independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si x selected from, and Si xis a silicon atom of a surface-attached moiety containing another silicon, or a silicon atom of a matrix silane attached to the surface of an optional IR-transmissive optical element, L 1 is an optional linking unit, X 1 is a group selected from -C(O)NH-, -NHC(O)-, -NHC(O)HN-, and -NHC(O)O-, $$ 1 represents attachment to the spacer moiety. 【0072】 According to one preferred embodiment, the surface-attached moiety (S) has the formula (S-I): / / -Y 1 -L 1 -X 1 -$$ 1 (S-I) having a structure according to wherein / / represents attachment to the surface of the IR-transmissive optical element, Y 1 is -O-Si(R 1 )2-, where R 1 are each independently selected from H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si x , and Si x is a silicon atom of a surface-attached moiety containing another silicon, or a silicon atom of a matrix silane attached to the surface of an optional IR-transmissive optical element, and optionally R 1 are each independently selected from C1-C6-alkoxy, -O- / / , and -O-Si x , and Si x is a silicon atom of a surface-attached moiety containing another silicon, or a silicon atom of an optional matrix silane attached to the surface of the IR-transmissive optical element, L 1 is a C1-C12 alkyl group, preferably a C1-C6 alkyl group (e.g., propyl), X 1is a group selected from -C(O)NH- and -NHC(O)-, preferably -NHC(O)-, $$ 1 represents attachment to the spacer moiety. 【0073】 According to another embodiment, the surface attachment moiety has the formula (S-II): / / -Y 3 -L 8 -$$ 1 (S-II) having a structure according to wherein / / represents attachment to the surface of the IR transmitting optical element, Y 3 is -S-, L 8 is a linking unit, preferably an optionally substituted alkyl group, for example an optionally substituted C1-C12 alkyl group, $$ 1 represents attachment to the spacer moiety. 【0074】 Preferably, the linker construct of formula (A) comprises the surface attachment moiety of formula (S-I). 【0075】 The spacer moiety (SP) can vary depending on (i) the procedure for synthesizing the linker construct and / or (ii) the procedure for attaching the molecular probe to the linker construct. For example, the molecular probe may be reacted with a pre-functionalized surface without pre-labeling the molecular probe. For example, the molecular probe may be reacted with the surface of the optical element functionalized with an aldehyde, an active ester, and / or a maleimide. 【0076】 According to one embodiment, the spacer moiety has the formula (SP-I) $$ 2 -L 2 -X 2 -L 3 -Y 2 -§§ 1 (SP-I) having a structure according to wherein $$ 2 represents attachment to the surface-attached portion, L 2 and L 3 are each independently an optional linking unit, X 2 is -(OCH2CH2)n 1 -, and n1 is an integer from 2 to 100, preferably 2 to 50, more preferably 2 to 25, even more preferably 2 to 16 (e.g., 3 to 6), Y 2 is selected from the group consisting of esters, hydrazones, amides, succinimides, and ring-opening products of succinimides, §§ 1 represents attachment to the molecular probe. 【0077】 Preferably, Y of formula (SP-I) 2 has one of the following structures: 【0078】 【Chemical formula】 wherein Q 1 is the NH, O or S atom of the molecular probe. When the molecular probe contains an amino acid (e.g., when the molecule is an antibody), Q 1 may be the NH, O or S of the amino acid of the molecular probe. For example, Q 1 may be the NH of the lysine side chain. 【0079】 The molecular probe may be attached to a pre-functionalized surface by a bioorthogonal ligation reaction. For example, the molecular probe may be ligated to a pre-functionalized surface by a click reaction, which is expected to result in the formation of an N-heterocyclic group in the spacer moiety in a preferred case. To prepare a molecular probe for a bioorthogonal ligation reaction, the molecular probe may be pre-labeled with a group suitable for the bioorthogonal ligation reaction. However, in cases where the molecular probe itself already contains such a functional group (e.g., an alkyne or azide as part of an unnatural amino acid of a protein), pre-labeling of the probe may not always be necessary. 【0080】 According to one preferred embodiment, the spacer moiety has the formula (SP-II) $$ 2 -L 2 -X 2 -L 3 -H 1 -L 4 -§§ 1 (SP-II) and has a structure according to wherein $$ 2 represents attachment to the surface attachment moiety, L 2 ~L 4 are each independently an optional linking unit, X 2 is -(OCH2CH2)n 1 -, where n1 is an integer from 2 to 100, preferably from 2 to 50, more preferably from 2 to 25, even more preferably from 2 to 16 (e.g., 3 to 6), H 1 is an optionally substituted N-heterocyclic group having a structure according to any one of the formulas (HET-I) to (HET-VI): 【0081】 【Chemical formula】 and is an optionally substituted N-heterocyclic group having a structure according to any one of them, && 1 represents attachment to L 3 or, if L 3 is absent, corresponds to X 2 ; && 2 represents attachment to L 4 or, if L 4 is absent, corresponds to §§ 1 ; R * is H, an optionally substituted alkyl group or an optionally substituted aryl group, preferably a C1-C6 alkyl group (e.g., methyl), ring A is an optionally substituted 8-membered carbocyclic compound or an optionally substituted 8-membered heterocycle, preferably an optionally substituted dibenzo-fused 8-membered N-heterocycle; §§ 1 represents attachment to another part of the linker construct or to the molecular probe. 【0082】 In one embodiment, §§ of formula (SP-II) 1 represents attachment to the molecular probe. 【0083】 According to one more preferred embodiment, the spacer part has a structure according to formula (SP-II) $$ 2 -L 2 -X 2 -L 3 -H 1 -L 4 -§§ 1 (SP-II) wherein, in the formula, $$ 2 represents attachment to the surface attachment part, L 2 ~L 4 are each independently an optional linking unit, X 2 is -(OCH2CH2)n 1- and n1 is an integer of 2 to 100, preferably 2 to 50, more preferably 2 to 25, even more preferably 2 to 16 (for example, 3 to 6). H 1 is an optionally substituted N - heterocyclic group having a structure according to formula (HET - II) or (HET - V): 【0084】 【Chemical formula】 wherein, in the formula, && 1 represents attachment to L 3 or, when L 3 is absent, corresponds to X 2 ; && 2 represents attachment to L 4 or, when L 4 is absent, corresponds to §§ 1 ; Ring A is an optionally substituted 8 - membered carbocyclic compound or an optionally substituted 8 - membered heterocycle, preferably an optionally substituted dibenzo - fused 8 - membered N - heterocycle; §§ 1 represents attachment to another part of the linker construct or to the molecular probe. 【0085】 L 2 may be a short linking unit that connects the surface - attaching moiety to the poly(alkylene oxide) of the spacer moiety. L 3 may be another short linker that connects the poly(alkylene oxide) to the N - heterocyclic group. For example, L 2 and L 3 , when present, may each independently be an alkyl group such as a C1 - C16 alkyl group or a C1 - C6 alkyl group. Preferably, L 2 is present and L 3 is absent. 【0086】 L 4may be a linking unit that connects an N - heterocyclic group to another part of the linker construct, for example, to a peptide compound in the peptide moiety. Alternatively, L 4 may be a linking unit that connects an N - heterocyclic group to a molecular probe. For example, L 4 may be a linking unit obtained by reacting an active ester (e.g., an NHS active ester) or a maleimide with a nucleophilic group in another compound, such as a peptide compound, a molecular probe, or a pre - labeled molecular probe. Preferably, L 4 contains an ester group, a hydrazone group, an amide group, or succinimide or their ring - opening products. 【0087】 According to one embodiment, the spacer moiety has a structure according to formula (SP - IIa) 【0088】 【Chemical formula】 having a structure according to wherein $$ 2 represents attachment to the surface - adhering moiety, n 1a is an integer from 1 to 16, preferably 2 to 4 (e.g., 2); X 2a is -(OCH2CH2)n 4a -, and n 4a is an integer from 2 to 16 (e.g., 3 to 6); X 3a is a bond or -CH2-; Ring A is an optionally substituted 8 - membered carbocyclic compound or an optionally substituted 8 - membered heterocycle, preferably an optionally substituted dibenzo - fused 8 - membered N - heterocycle; X 4a is a bond, O, -C(O)- or a carbon atom that forms a cyclopropyl group with two adjacent carbons of ring A; n 2a is an integer from 1 to 5; X 5a is a bond or -(OCH2CH2)n5a - and n 5a is an integer from 1 to 16; X 6a is a bond or -(CH2)n 6a - and n 6a is an integer from 1 to 5; Y 2a is an ester, hydrazone, amide, or succinimide or a ring-opening product thereof, each of which is covalently bonded to another part of the linker construct or the molecular probe, and preferably, Y 2a has the following structure: 【0089】 【Chemical formula】 has one of the following, where Q 3 is an NH, O, or S atom of another part of the linker construct or the molecular probe. 【0090】 According to one embodiment, the spacer part has a structure according to formula (SP-IIb): 【0091】 【Chemical formula】 or is its [2+3] cycloaddition regiochemical isomer, wherein, $$ 2 represents attachment to the surface attachment part, n 1b is an integer from 1 to 16, preferably from 2 to 4 (e.g., 2); X 2b is -(OCH2CH2)n 4b - and n 4b is an integer from 2 to 16 (e.g., 3 to 6); X 3b is a bond or -CH2-; R x is 1 to 4 optional substituents (e.g., C1-C6 alkyl groups); Z 1 is N, O, or CH, Z2 is CH2, CH, or C(O), X 4b is a bond, O, -C(O)- or Z 1 and Z 2 is a carbon atom that forms a cyclopropyl group; n 3b is an integer from 1 to 5; X 5b is a bond or -(OCH2CH2)n 5b - and n 5b is an integer from 1 to 16; X 6b is a bond or -(CH2)n 6b - and n 6b is an integer from 1 to 5; Y 2b is an ester, amide, hydrazone, or succinimide or an open-ring product thereof, each of which is covalently bonded to another part of the linker construct or a molecular probe, preferably, Y 2b has the following structure: 【0092】 【Chemical formula】 has one of the following, where Q 3 is an NH, O or S atom of another part of the linker construct or a molecular probe. 【0093】 According to one embodiment, the spacer part has a structure according to formula (SP-IIc): 【0094】 【Chemical formula】 has a structure according to or is a [2+3] addition cyclization positional isomer thereof, wherein, $$ 2 represents attachment to the surface attachment part, n 1c is an integer from 2 to 16 (e.g., 3 to 6); Y 2cis an ester, amide, hydrazone, or succinimide or a ring-opened product thereof, each of which is covalently bonded to another part of the linker construct or to the molecular probe, preferably, Y 2c has the following structure: 【0095】 [Chemical formula] and has one of the following, where Q 3 is an NH, O, or S atom of another part of the linker construct or of the molecular probe. 【0096】 In each one of the above formulas (SP-IIa) to (SP-IIc), Y 2a , Y 2b , and Y 2c are each more preferably 【0097】 [Chemical formula] where Q 3 is an NH or O atom of another part of the linker construct or of the molecular probe. 【0098】 The linker construct may optionally include an additional part that connects the spacer part and the molecular probe. 【0099】 In one embodiment, the linker construct further includes a peptide part (Pep) that covalently bonds the spacer part (SP) and the molecular probe. The peptide part includes a peptide compound as defined above herein and an optional linking unit that connects the peptide compound to the spacer part and the molecular probe. The linking unit may be any linking unit suitable for attaching the peptide compound to another organic compound. The linking unit may be, but is not limited to, for example, an ester, an amide, a thioester, etc. 【0100】 When the peptide moiety is present in the linker construct, the linker construct generally has the formula (B): / / -(S)-(SP)-(Pep)-\\ (B) which can be defined by a structure according to wherein / / represents attachment to the surface of the IR transmissive optical element, (S) represents the surface attachment moiety, (SP) represents the spacer moiety, (PEP) is a peptide moiety containing a peptide compound as defined above in this specification, \\ represents attachment to the molecular probe. 【0101】 Regarding the definitions of the surface attachment group (S) and the spacer moiety (SP) in formula (B), reference is made to the embodiments and preferred embodiments defined above in this specification in connection with the linker construct according to formula (A). 【0102】 Preferably, the surface attachment group (S) has a structure according to formula (S-I), and the spacer moiety (SP) has a structure according to any one of formulas (SP-II) and (SP-IIa)-(SP-IIc). 【0103】 When the peptide moiety is present in the linker construct, it is expected to be understood that §§ of formula (SP-II) 1 represents attachment to the peptide compound of the peptide moiety. 【0104】 Furthermore, when the peptide moiety is present in the linker construct, each one of Y of formulas (SP-IIa)-(SP-IIc) 2a ~Y 2c represents an ester, hydrazone, amide, or succinimide or a ring-opened product thereof, and each of these is expected to be understood to be covalently bonded to the peptide compound of the peptide moiety. 【0105】 According to one embodiment, the peptide moiety (Pep) has the formula (PEP-I): §§2 -P 1 -L 5 -H 2 -L 6 -## 1 (PEP-I) has a structure according to wherein §§ 2 represents attachment to the spacer moiety (SP), P 1 is a peptide compound of the peptide moiety, L 5 and L 6 are each independently an optional linking unit, H 2 is an N - heterocyclic group having a structure according to any one of formulas (HET - VII) to (HET - XII): 【0106】 【Chemical formula】 an optionally substituted N - heterocyclic group having a structure according to any one of them, %% 1 is L 5 represents attachment to L or, when L 5 is absent, corresponds to Z 1 ; %% 2 is L 6 represents attachment to L or, when L 6 is absent, corresponds to ## 1 ; R ** is H, an optionally substituted alkyl group or an optionally substituted aryl group, preferably a C1 - C6 alkyl group (e.g., methyl), Ring B is an optionally substituted 8 - membered carbocyclic compound or an optionally substituted 8 - membered heterocycle, preferably an optionally substituted dibenzo - fused 8 - membered N - heterocycle; ## 1 represents attachment to the molecular probe. 【0107】 According to one embodiment, the peptide moiety (Pep) has the structure according to formula (PEP-I): §§ 2 -P 1 -L 5 -H 2 -L 6 -## 1 (PEP-I) and has a structure according to wherein §§ 2 represents attachment to the spacer moiety (SP), P 1 is a peptide compound of the peptide moiety, L 5 and L 6 are each independently a linking unit, H 2 is an optionally substituted N - heterocyclic group having a structure according to any one of formulas (HET - VII) to (HET - XII): 【0108】 【Chemical formula】 and is an optionally substituted N - heterocyclic group having a structure according to any one of them, %% 1 is L 5 represents attachment to, %% 2 is L 6 represents attachment to, R ** is H, an optionally substituted alkyl group or an optionally substituted aryl group, preferably a C1 - C6 alkyl group, Ring B is an optionally substituted 8 - membered carbocyclic compound or an optionally substituted 8 - membered heterocycle, preferably an optionally substituted dibenzo - fused 8 - membered N - heterocycle; ## 1 represents attachment to the molecular probe. 【0109】 The peptide compound P 1The preferred embodiments have been described above in connection with peptide compounds of optional peptide moieties. These embodiments and preferred embodiments are also disclosed in combination with P of formula (PEP-I) 1 and are also disclosed in combination with 【0110】 Linking unit L 5 and L 5 are not particularly limited. The linking unit L 5 and L 6 may each independently contain a short alkyl chain (e.g., a C1-C6 alkyl chain) and optionally a short PEG group (e.g., a PEG group having 2-10 glycol repeating units). 【0111】 Preferably, L 5 and L 6 are each independently a linking unit connected to the peptide compound and / or the molecular probe by an ester, hydrazone, amide, succinimide or a ring-opening product thereof. 【0112】 According to one embodiment, the peptide moiety (Pep) has a structure according to formula (PEP-I): §§ 2 -P 1 -L 5 -H 2 -L 6 -## 1 (PEP-I) wherein in the formula §§ 2 represents attachment to the spacer moiety (SP), P 1 is a peptide compound of the peptide moiety, “-L 5 -H 2 -L 6 -## 1 ” has a structure according to formula (sub-PEP-a): 【0113】 【Chemical formula】 and has a structure according to In the formula, U is an ester, hydrazone, amide, or succinimide or a ring-opening product thereof, each of which is covalently bonded to the peptide compound P 1 and, V 1a is (CH2)m 1a where m 1a is an integer from 1 to 10, preferably from 1 to 4, V 2a is (OCH2CH2)m 2a where m 2a is an integer from 1 to 15, preferably from 2 to 10, V 3a is a bond or CH2, preferably a bond, W 1a is a linking unit, Ring B is an optionally substituted 8-membered carbocyclic compound or an optionally substituted 8-membered heterocycle, preferably an optionally substituted dibenzo-fused 8-membered N-heterocycle; ## 1 represents attachment to a molecular probe. 【0114】 According to one embodiment, the peptide moiety (Pep) has the formula (PEP-I): §§ 2 -P 1 -L 5 -H 2 -L 6 -## 1 (PEP-I) has a structure according to In the formula, §§ 2 represents attachment to a spacer moiety (SP), P 1 is a peptide compound of the peptide moiety, “-L 5 -H 2 -L 6 -## 1 ” is of the formula (sub-PEP-b): 【0115】 [Chemical formula] has a structure according to wherein U is an ester, hydrazone, amide, or succinimide or a ring-opening product thereof, each of which is covalently bonded to the peptide compound P 1 ; V 1b is (CH2)m 1b where m 1b is an integer from 1 to 10; V 2b is a bond; V 3b is C(O); W 1b is a linking unit; Ring B is an optionally substituted 8-membered carbocyclic compound or an optionally substituted 8-membered heterocycle, preferably an optionally substituted dibenzo-fused 8-membered N-heterocycle; ## 1 represents attachment to a molecular probe. 【0116】 According to one embodiment, the peptide moiety (Pep) has a structure according to formula (PEP-I): §§ 2 -P 1 -L 5 -H 2 -L 6 -## 1 (PEP-I) has a structure according to wherein §§ 2 represents attachment to a spacer moiety (SP), P 1 is a peptide compound of the peptide moiety, “-L 5 -H 2 -L 6 -## 1 ” is of formula (sub-PEP-c): 【0117】 [Chemical formula] has a structure according to, or is a [2+3] addition cyclization positional isomer thereof, wherein, U is an ester, hydrazone, amide, or succinimide or a ring-opening product thereof, each of which is covalently bonded to the peptide compound P 1 and V 1c is (CH2)m 1c where m 1c is an integer from 1 to 10, preferably from 1 to 4, V 2c is (OCH2CH2)m 2c where m 2c is an integer from 1 to 15, preferably from 2 to 10, V 3c is a bond or CH2, preferably a bond, W 1c is a linking unit, R z is one to four optional substituents, preferably R z is absent, B 1 is N or CH, preferably N, B 2 is CH2, ## 1 represents attachment to a molecular probe. 【0118】 According to one embodiment, the peptide moiety (Pep) has a structure according to formula (PEP-I): §§ 2 -P 1 -L 5 -H 2 -L 6 -## 1 (PEP-I) and has a structure according to, wherein, §§ 2 represents attachment to a spacer moiety (SP), P 1 is a peptide compound of the peptide moiety, “-L5 -H 2 -L 6 -## 1 " is of the formula (sub-PEP-d): 【0119】 【Chemical formula】 has a structure according to or is its [2+3] addition cyclization positional isomer, wherein, U is an ester, hydrazone, amide, or succinimide or their ring-opening products, each of which is covalently bonded to the peptide compound P 1 and is covalently bonded to, V 1d is (CH2)m 1d where m 1d is an integer from 1 to 10, V 2d is a bond, V 3d is C(O), W 1d is a linking unit, preferably a linking unit containing (i) a PEG linker and (ii) an ester, amide, or succinimide or their ring-opening products, each of which is covalently bonded to the molecular probe, R z is 1 to 4 optional substituents, preferably R z is absent, B 1 is N, B 2 is CH2, ## 1 represents attachment to the molecular probe. 【0120】 Preferably, the substituent U in any one of the above formulas (sub-PEP-a) to (sub-PEP-d) is: 【0121】 【Chemical formula】 is one of, wherein Q 4 is the peptide compound P1 is the NH, O, or S of the amino acid. 【0122】 More preferably, the substituent U in any one of the above formulas (sub-PEP-a) to (sub-PEP-d) is 【0123】 【Chemical formula】 wherein Q 4 is the NH or O of the amino acid of the peptide compound P 1 is the NH or O of the amino acid of the peptide compound P. 【0124】 Molecular probe The surface-functionalized optical element includes a molecular probe. 【0125】 The molecular probe may be attached to the linker construct by a ligation group. The ligation group may be, but is not limited to, an ester, hydrazone, amide, hydrazone, succinimide or ring-opened product of succinimide, or a group obtainable by a bioorthogonal ligation reaction (e.g., an N-heterocyclic group as defined above in this specification). 【0126】 Preferably, the molecular probe is covalently bonded to the linker construct by a bioorthogonal ligation reaction, or by a group obtainable by an ester, or an amide, or succinimide or a ring-opened product thereof. 【0127】 For example, the molecular probe has the following structure: 【0128】 【Chemical formula】 may be covalently bonded to the linker construct by one of the following, wherein Q 1 is the NH, O, or S atom of the molecular probe, and "\\" represents the attachment of the remaining linker construct. Preferably, the molecular probe has the following group: 【0129】 [Chem.] is attached to the linker construct by, wherein Q 1 is the NH or O atom of the molecular probe, and "\\" represents the attachment of the remaining linker construct. 【0130】 The molecular probe is not particularly limited and can be selected by those skilled in the art according to the target analyte to be detected and / or analyzed, and / or the chemical interaction of the target to be detected or analyzed. For example, the molecular probe may be a molecular probe known in the art to be useful in ATR-IR spectroscopy and biosensors using said spectroscopy. 【0131】 According to one embodiment, the molecular probe is an antigen, antibody, antibody fragment, fusion protein with an antibody or antibody fragment, conjugate with an antibody or antibody fragment, protein complex optionally containing an antibody fragment or its fusion protein, anticalin, nanobody, organic small molecule, drug, nucleic acid, aptamer, lipid, carbohydrate, peptide, or a mixture thereof. 【0132】 According to one embodiment, the molecular probe is an antigen-binding protein, and optionally, an antigen-binding protein selected from an antibody, antibody fragment, fusion protein with an antibody or antibody fragment, conjugate with an antibody or antibody fragment, or protein complex optionally containing an antibody fragment or its fusion protein, anticalin, nanobody, and mixtures thereof. 【0133】 According to one preferred embodiment, the molecular probe is an anti-amyloid β antibody, anti-alpha synuclein antibody, anti-tau antibody, anti-TDP-43 antibody, or a fragment, fusion protein and / or conjugate of said antibody. 【0134】 The anti-amyloid β antibody may be selected from the following list: 2E9, H31L21, 11A50-B10, 12B2, 4G8, 11H3, MOAB-2, anti-Aβ25-35, A8978, 5C3, 8G7, 6G12, 1E8, and 32A1. The anti-alpha-synuclein antibody may be 4B12, AKS5946, S5566. The anti-tau antibody may be tau-5 or tau-396. The anti-TDP-43 antibody may be 1HCLC. 【0135】 According to one embodiment, the molecular probe is an anti-amyloid β antibody, or a fragment, fusion protein, and / or conjugate thereof. 【0136】 According to one embodiment, the molecular probe is an anti-alpha-synuclein antibody, or a fragment, fusion protein, and / or conjugate thereof. 【0137】 According to one embodiment, the molecular probe is capable of forming a complex with a protein associated with or potentially causing a protein misfolding disease. Protein misfolding diseases are also referred to in the art as proteopathies, which are a class of diseases in which one or more proteins misfold and / or become structurally abnormal, which can disrupt the function of cells, tissues, and / or organs. Protein misfolding diseases and proteins associated with protein misfolding diseases are known to those skilled in the art, and examples thereof include, but are not limited to, amyloid beta peptide, tau protein, alpha-synuclein, TDP-43, and huntingtin. 【0138】 According to one preferred embodiment, the molecular probe is capable of forming a complex with a target analyte selected from the group consisting of amyloid beta (Aβ) peptide and its isoforms, alpha-synuclein, tau protein, TDP-43, human islet amyloid polypeptide (hiAPP), prion protein, and / or p53. 【0139】 The amyloid beta (Aβ) peptide may be a monomer, oligomer or fibrillar amyloid beta (Aβ) peptide. 【0140】 Matrix silane The surface-functionalized optical element may further contain matrix silane, and at least a part of the surface of the IR-transmissive optical element is covalently bonded to the matrix silane. 【0141】 According to one embodiment, the matrix silane contains a poly(alkylene oxide) group, preferably a poly(ethylene glycol) group, and an inert end group. The inert end group may be, but is not limited to, a terminal alkyl group such as a terminal C1-C6 alkyl group (e.g., methyl), or a terminal alkoxy group such as a terminal C1-C6 alkoxy group (e.g., methoxy). 【0142】 The matrix silane can function as a matrix on the surface of the IR-transmissive optical element, reducing non-specific binding of the medium or sample components to the surface and further contributing to the stability of the surface functionalization. Furthermore, the use of matrix silane allows for fine-tuning the amount of linker construct to be attached to the surface of the optical element and for spacing the linker constructs on the surface of the optical element. In turn, spacing the linker constructs allows for spacing the molecular probes on the surface of the optical element, thereby improving the interaction and / or detection between the molecular probe and the target analyte, e.g., the interaction and / or detection between an antibody as the molecular probe and the target antigen. 【0143】 According to one preferred embodiment, at least a part of the surface of the optical element is covalently bonded to the matrix silane, and the matrix silane has the structure according to formula (MA-a): / / -(S)-(PAO spacer)-(cap) (MA-a) having the structure according to wherein 「 / / 」 represents the adhesion to the surface of the IR-transmissive optical element, (S) represents the surface-adhered portion, (PAO spacer) represents the spacer portion containing a poly(alkylene oxide) group, (cap) represents an inert terminal group, preferably a terminal C1-C6 alkyl group (e.g., methyl) or a terminal C1-C6 alkoxy group (e.g., methoxy). 【0144】 The matrix silane may have the same surface-adhered portion as the linker construct or a different surface-adhered portion. According to one embodiment, the matrix silane has the same surface-adhering group as the linker construct. 【0145】 According to one embodiment, the surface-adhered portion (S) of formula (MA-a) has the structure according to formula (S-MA): / / -Y 11 -L 11 -X 11 -$$ x (S-MA) has a structure according to, wherein, / / represents the adhesion to the surface of the IR-transmissive optical element, Y 11 is -O-Si(R 11 )2-, and R 11 are each independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si y selected from, and Si y is a silicon atom of another silicon-containing surface-adhered portion or a silicon atom of a matrix silane adhered to the surface of an optional IR-transmissive optical element, L 11 is an optional linking unit, X 11 is a group selected from -C(O)NH-, -NHC(O)-, -NHC(O)HN-, and -NHC(O)O-, $$ xrepresents the attachment to a spacer moiety containing a poly(alkylene oxide) group. 【0146】 According to one preferred embodiment, the surface attachment moiety (S) of formula (MA-a) has the structure of formula (S-MA): / / -Y 11 -L 11 -X 11 -$$ x (S-MA) having a structure according to wherein / / represents the attachment to the surface of the IR transmissive optical element, Y 11 is -O-Si(R 11 )2-, and R 11 are each independently selected from H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si y , and Si y is the silicon atom of another silicon-containing surface attachment moiety or the silicon atom of a matrix silane attached to the surface of an optional IR transmissive optical element, and optionally R 11 are each independently selected from C1-C6-alkoxy, -O- / / , and -O-Si y , and Si y is the silicon atom of another silicon-containing surface attachment moiety or the silicon atom of a matrix silane attached to the surface of an optional IR transmissive optical element, L 11 is a C1-C12 alkyl group, preferably a C1-C6 alkyl group, X 11 is a group selected from -C(O)NH- and -NHC(O)-, preferably -NHC(O)-, $$ x represents the attachment to a spacer moiety containing a poly(alkylene oxide) group. 【0147】 The spacer (POA spacer) defined by formula (MA-a) contains a poly(alkylene oxide) group. The alkylene subunits of the poly(alkylene oxide) may be optionally substituted. The poly(alkylene oxide) may be, but is not limited to, poly(ethylene oxide), poly(propylene oxide), poly(butylene oxide), or a block copolymer thereof. 【0148】 Preferably, the poly(alkylene oxide) is poly(ethylene oxide), which is also referred to in the art as polyethylene glycol or PEG. According to one preferred embodiment, the poly(alkylene oxide) is a polyethylene glycol having 2 to 100 glycol repeat units, more preferably 2 to 50 repeat units, even more preferably 2 to 25 repeat units, even more preferably 2 to 16 repeat units, for example 2 to 8 glycol repeat units or for example 3 to 6 glycol repeat units. 【0149】 According to one embodiment, at least a part of the surface of the IR transmitting optical element is covalently bonded to a matrix silane, and the matrix silane has the formula (MA-b): / / -Y 11 -L 11 -X 11 -X 12 -X 13 -T 1 (MA-b) having a structure according to wherein / / represents attachment to the surface of the IR transmitting optical element, Y 11 is -O-Si(R 11 )2-, and R 11 are each independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si y selected from, and Si yis a silicon atom of a surface-attached moiety containing another silicon or a silicon atom of a matrix silane attached to the surface of an optional IR-transmissive optical element, and optionally R 11 is, independently of one another, C1-C6-alkoxy, -O- / / , and -O-Si y selected from, and Si y is a silicon atom of a surface-attached moiety containing another silicon or a silicon atom of an optional matrix silane attached to the surface of an IR-transmissive optical element, L 11 is a C1-C12 alkyl group, preferably a C1-C6 alkyl group, X 11 is a group selected from -C(O)NH- and -NHC(O)-, preferably -NHC(O)-, X 12 is a bond or an alkyl group, preferably a C1-C6 alkyl group, X 13 is -(OCH2CH2)k-, where k is an integer from 2 to 16 (for example 3 to 6); T 1 is an alkyl group or an alkyloxy group, preferably a C1-C6 alkyl group (for example methyl) or a C1-C6-alkoxy group (for example methoxy). 【0150】 Optical biosensor In one aspect, the present invention provides an optical biosensor comprising a surface-functionalized optical element as defined herein. 【0151】 A biosensor is an analytical device for the detection of a target analyte. A biosensor comprises a bioreceptor element (molecular probe) and a transducer element. The bioreceptor element (molecular probe) can interact with the target analyte to create a physicochemical change that is converted into a signal measurable by the transducer element. The signal is measured by optical spectroscopy such as, but not limited to, infrared ATR spectroscopy, transmission spectroscopy, Raman spectroscopy, colorimetric microscopy, fluorescence microscopy, luminescence microscopy, or combinations of these techniques. 【0152】 Thus, the optical biosensor according to the present invention can be used in conjunction with infrared ATR spectroscopy, transmission spectroscopy, Raman spectroscopy, colorimetric microscopy, fluorescence microscopy, luminescence microscopy, or combinations of these techniques. 【0153】 According to one preferred embodiment, the device is an IR transmission-based biosensor or an ATR-IR-based biosensor, and more preferably, the device is an ATR-IR-based biosensor. Such devices are known in the art and are described, for example, in Nabers et al, Anal. Chem. 2016, 88, 2755-2762. 【0154】 Process for preparing a surface-functionalized optical element In one aspect, the present invention provides a process for preparing a surface-functionalized optical element, preferably a process for preparing a surface-functionalized optical element according to the present invention. The process comprises (a) providing an IR-transmissive optical element, (b) reacting at least a portion of the surface of the optical element with a compound containing poly(alkylene oxide) and includes. 【0155】 In step a), an IR-transmissive optical element is provided. The IR-transmissive optical element is preferably the IR-transmissive optical element as defined above herein in connection with the surface-functionalized optical element of the present invention. 【0156】 In step b), at least a portion of the surface of the IR-transmissive optical element reacts with a compound containing poly(alkylene oxide). In step b), the compound containing poly(alkylene oxide) reacts with the surface of the IR-transmissive optical element to create a covalent bond. 【0157】 In a preferred embodiment, the compound containing poly(alkylene oxide) is a silane containing poly(alkylene oxide) or a thiol containing poly(alkylene oxide), more preferably a silane containing poly(alkylene oxide). In the latter case, the silane of the silane containing poly(alkylene oxide) reacts with the surface of the IR transmissive optical element to create a covalent bond. 【0158】 In one more preferred embodiment, the compound containing poly(ethylene oxide) is a silane containing poly(ethylene oxide) or a thiol containing poly(ethylene oxide), even more preferably a silane containing poly(ethylene oxide). 【0159】 It is preferred that the surface of the optical element is first pre-functionalized and subsequently a linking unit of a molecular probe or a linker construct is attached onto the pre-functionalized surface. The process according to the invention can be further defined by one of the synthetic procedures (A) and (B) defined below in the present specification: 【0160】 Synthetic procedure (A) Synthetic procedure (A) relates to a procedure for at least partially pre-functionalizing the surface of an IR transmissive optical element with a group selected from nucleophilic reactive groups. 【0161】 In synthetic procedure (A), the compound containing poly(alkylene oxide), preferably the silane containing poly(alkylene oxide), contains a nucleophilic reactive group suitable for directly attaching a molecular probe. 【0162】 According to one embodiment, the compound containing poly(alkylene oxide) in step b), preferably the silane containing poly(alkylene oxide), contains a group selected from nucleophilic reactive groups selected from aldehyde, carboxylic acid, ester, active ester and maleimide. 【0163】 Accordingly, according to one embodiment, an optical element having a surface that is at least partially pre-functionalized, preferably pre-functionalized by a group selected from nucleophilic reactive groups as defined above herein, is obtained in step b). 【0164】 Synthesis procedure (A) further includes step c) of reacting a molecular probe with the at least partially pre-functionalized surface of the optical element obtained in step b). 【0165】 For example, in the case where the molecular probe contains one or more amine groups, for example as part of one or more lysine groups of a peptide / protein, the molecular group may be reacted with the surface of an optical element pre-functionalized by a compound containing a nucleophilic reactive group (for example an NHS-ester group), preferably a silane. 【0166】 According to one embodiment, the process is (a) providing an optical element as defined herein,[ (b) reacting at least a part of the surface of the optical element with a compound containing poly(alkylene oxide), preferably a silane containing poly(alkylene oxide), to obtain an optical element, the compound containing a group selected from nucleophilic reactive groups, preferably a group selected from aldehyde, carboxylic acid, ester, active ester and maleimide, and the optical element obtained in step b) has a surface that is at least partially pre-functionalized, the step,[ (c) reacting a molecular probe with the at least partially pre-functionalized surface of the optical element obtained in step (c) to obtain a surface-functionalized optical element according to the invention including. 【0167】 Synthesis procedure (B) Synthesis procedure (B) relates to a procedure for pre - functionalizing at least partially the surface of an IR - transmissive optical element with a group selected from bio - orthogonal reactive groups. "Bio - orthogonal reactive groups" are known to those skilled in the art and include, but are not limited to, alkyne, strained cycloalkyne, strained cycloalkene, azide, tetrazine, nitrone, norbornene, nitrile oxide, oxanorbonadiene, and tetrazole. 【0168】 "Strained cycloalkyne" is known to those skilled in the art and examples thereof include, but are not limited to, 8 - membered cycloalkynes. Examples of "strained cycloalkene" include, but are not limited to, trans - cyclooctene. 【0169】 In synthesis procedure (B), a compound containing poly(alkylene oxide), preferably a silane containing poly(alkylene oxide), contains a bio - orthogonal reactive group suitable for attaching the linking unit of the linker construct. Synthesis procedure (B) is preferred. 【0170】 According to one embodiment, the compound containing poly(alkylene oxide) in step b), preferably the silane containing poly(alkylene oxide), contains a group selected from bio - orthogonal reactive groups, preferably a group selected from alkyne, strained cycloalkyne, strained cycloalkene, azide, and tetrazine. 【0171】 Thus, according to this embodiment, an optical element having a surface that is at least partially pre - functionalized with a group selected from bio - orthogonal reactive groups, preferably a group selected from alkyne, strained cycloalkyne, strained cycloalkene, azide, and tetrazine, is obtained in step b). 【0172】 According to one embodiment, step b) comprises reacting at least a part of the surface of the optical element with formula (C - A1) Y a -L a -X a (C-A1) comprising the step of reacting with a compound containing a poly(alkylene oxide) according to wherein Y a is -SH or -SiZ a 3, and each Z a is independently selected from -O-(CH2)r-CH3, -(CH2)t-CH3, and halogen, r is an integer from 0 to 4, and t is an integer from 0 to 6, L a is a linking moiety containing a poly(alkylene oxide), X a is -N3, a cyclotransalkene group, an alkyne group, or 【0173】 【Chemical formula】 and R is an optional substituent, preferably an optional C1-C6 alkyl substituent (such as methyl), preferably, X a is -N3. 【0174】 The cyclotransalkene group may be, but is not limited to, an optionally substituted 8-membered cyclotransalkene optionally containing one or more heteroatoms. 【0175】 Suitable alkyne groups for the substituent X a are alkyne groups containing structural units of DBCO, DIBO, DIFO, or BCN. These abbreviations are well-known in the art. For illustration, DBCO is 【0176】 【Chemical formula】 and DIBO is 【0177】 【Chemical formula】 and DIFO is 【0178】 【Chem.】 is as follows. 【0179】 According to one preferred embodiment, step b) comprises reacting at least a part of the surface of the optical element with a compound containing a poly(alkylene oxide) according to formula (C-A1) Y a -L a -X a (C-A1) wherein, in the formula, Y a is -SiZ a 3, and each Z a is independently selected from -O-(CH2)r-CH3, -(CH2)t-CH3, and halogen, r is an integer from 0 to 4, t is an integer from 0 to 6, and preferably each Z a is -OCH3 or -OCH2CH3, L a is a linking moiety containing poly(alkylene oxide), X a is -N3, a cyclotransalkene group, an alkyne group, or 【0180】 【Chem.】 wherein, R is an optional substituent, preferably an optional C1-C6 alkyl substituent (e.g., methyl), preferably, X a is -N3. 【0181】 According to one embodiment, step b) comprises reacting at least a part of the surface of the optical element with a compound of formula (C-A2) Y a -(CH2)u-X a1 -(CH2)v-X a2 -X a3 -X a (C-A2) reacting with a compound containing a poly(alkylene oxide) according to wherein Y a is -SH or -SiZ a 3, and each Z a is independently selected from -O-(CH2)r-CH3, -(CH2)t-CH3, and halogen, r is an integer from 0 to 4, t is an integer from 0 to 6, u is an integer from 1 to 6; X a1 is a bond, -C(O)NH- or -NHC(O)-; v is an integer from 1 to 16; X a2 is -(OCH2CH2)n 1 -, and n 1 is an integer from 1 to 16; X a3 is a bond or -CH2-; X a is -N3, a cyclotransalkene group, an alkyne group, or 【0182】 【Chemical formula】 wherein R is an optional substituent, preferably an optional C1-C6 alkyl substituent (e.g., methyl), preferably, X a is -N3. 【0183】 According to one preferred embodiment, step b) is of the formula (C-A2) Y a -(CH2)u-X a1 -(CH2)v-X a2 -X a3 -X a (C-A2) reacting at least a part of the surface of an optical element according to with a compound containing a poly(alkylene oxide), wherein Y a is -SiZ ais 3, and each Z a is independently selected from -O-(CH2)r-CH3, -(CH2)t-CH3, and halogen, where r is an integer from 0 to 4 and t is an integer from 0 to 6. Preferably, each Z a is -OCH3 or -OCH2CH3, u is an integer from 1 to 6; X a1 is a bond, -C(O)NH-, or -NHC(O)-; v is an integer from 1 to 16; X a2 is a bond or -(OCH2CH2)n 1 -, where n 1 is an integer from 1 to 16; X a3 is a bond or -CH2-; X a is -N3, a cyclotransalkene group, an alkyne group, or 【0184】 【Chemical formula】 wherein R is an optional substituent, preferably an optional C1-C6 alkyl substituent (such as methyl), Preferably, X a is -N3. 【0185】 In a specific embodiment, the compound containing poly(alkylene oxide) in step b) has the following structure: 【0186】 【Chemical formula】 may have. 【0187】 The pre-functionalized optical element can then be reacted with a molecular probe (synthesis procedure (B1)) or a pre-labeled molecular probe (synthesis procedure (B2)) in step c) to obtain the surface-functionalized optical element of the present invention. 【0188】 Alternatively, the pre-functionalized optical element can then be reacted with the linking unit of the linker construct to further prepare the surface of the optical element for the attachment of molecular probes (Synthesis Procedure (B3)). 【0189】 Synthesis Procedure (B1) In Synthesis Procedure (B1), the pre-functionalized optical element obtained in step (b) of Synthesis Procedure (B) is then reacted in step (c) with a molecular probe comprising one or more bioorthogonal reactive groups, such as azides, as part of a non-natural amino acid of the peptide / protein. In step (c), a surface-functionalized optical element according to the invention is obtained. 【0190】 The molecular probe reacted in step (c) comprises one or more bioorthogonal reactive groups suitable for reacting with the bioorthogonal reactive groups on the pre-functionalized surface of the optical element. Such pairs of bioorthogonal reactive groups are known to those skilled in the art and examples thereof include, but are not limited to, azide / alkyne, azide / strained alkyne, trans-alkene / tetrazene. 【0191】 Synthesis Procedure (B2) In Synthesis Procedure (B2), the pre-functionalized optical element obtained in step (b) of Synthesis Procedure (B) is then reacted in step (c) with a pre-labeled molecular probe. In step (c), a surface-functionalized optical element according to the invention is obtained. 【0192】 Thus, according to one embodiment, the process comprises step (c) of reacting the pre-functionalized surface of the optical element with a pre-labeled molecular probe. The pre-labeled molecular probe is preferably pre-labeled with a bioorthogonal reactive group suitable for reacting with the bioorthogonal reactive groups on the pre-functionalized surface of the optical element. Such pairs of bioorthogonal reactive groups are known to those skilled in the art and examples thereof include, but are not limited to, azide / alkyne, azide / strained alkyne, trans-alkene / tetrazene. 【0193】 The bioorthogonal reactive group can be covalently attached to the molecular probe through a linking unit. For example, pre-labeling the molecular probe may be performed by reacting the molecular probe with a labeling compound containing (i) a bioorthogonal reactive group and (ii) a nucleophilic reactive group (e.g., NHS active ester), in which case the nucleophilic reactive group reacts with the molecular probe. 【0194】 According to one embodiment, the pre-labeled molecular probe contains an alkyne group and optionally contains an alkyne group containing a structural unit of DBCO, DIBO, DIFO, or BCN. 【0195】 Synthesis procedure (B3) In synthesis procedure (B3), the surface-functionalized optical element of the present invention can be obtained in a single step (c) without directly reacting the pre-functionalized optical element obtained in step (b), but step (c) may include one or more of additional steps (c-1) to (c-5). 【0196】 In synthesis procedure (B3), the pre-functionalized optical element obtained in step (b) of synthesis procedure (B) is then reacted in step (c-1) with (i) a bioorthogonal reactive group suitable for reacting the bioorthogonal reactive group on the pre-functionalized surface of the optical element, and (ii) a linking unit precursor containing a nucleophilic reactive group as defined herein. 【0197】 The bioorthogonal reactive group (i) of the linking unit precursor is preferably selected from azide, alkyne group, trans-alkene group, and tetrazene. The nucleophilic reactive group (ii) of the linking unit precursor is preferably selected from aldehyde, carboxylic acid, ester, active ester, and maleimide, and more preferably NHS active ester or TFP active ester. 【0198】 In one specific example, the linking unit precursor used in step (c-1) has the following structure: 【0199】 [Chemistry] has 【0200】 In step (c-1), an optical element having a surface that is at least partially pre-functionalized by a nucleophilic reactive group is obtained. 【0201】 The pre-functionalized optical element obtained in step (c-1) can then be used in step (c-2) of the process to attach a molecular probe. Thus, according to one embodiment, the process includes step (c-2) of reacting a molecular probe with the optical element obtained in step (c-1) to obtain a surface-functionalized optical element according to the present invention. The attachment in step (c-2) is achieved by reacting a molecular probe (e.g., the H2N-group of the lysine side chain of the molecular probe) with the nucleophilic reactive group of the optical element obtained in step (c-1). 【0202】 Alternatively, the pre-functionalized optical element obtained in step (c-1) can then be used in step (c-3) of the process to attach a peptide compound of a peptide moiety. The attachment in step (c-3) is achieved by reacting a molecular probe or a peptide compound with the nucleophilic reactive group of the optical element obtained in step (c-1). 【0203】 According to another embodiment, the process includes step (c-3) of reacting a peptide compound with the optical element obtained in step (c-1) to obtain an optical element having a surface that is at least partially functionalized by the peptide compound. It can be understood that the peptide-functionalized optical element obtained in step (c-3) has a peptide layer in which at least a part of the surface of the optical element is covalently bonded. This peptide layer may have the function of a blocking layer in the final surface-functionalized optical element. 【0204】 The peptide compound of the optical element functionalized with the peptide obtained in step (c-3) can then be reacted with a second linker unit precursor in step (c-4). The second linker unit precursor may be any precursor suitable for attaching a molecular probe (pre-labeled or un-pre-labeled) to the peptide-functionalized surface. Step (c-4) provides a pre-functionalized surface, which can then be reacted with a molecular probe in step (c-5) to provide the surface-functionalized optical element of the present invention. 【0205】 Typically, the second linker unit precursor is expected to have two reactive groups, one of which is used to attach the second linker unit precursor to the peptide compound, and the other of which is used as an attachment point for the molecular probe. 【0206】 According to one embodiment, the process includes step (c-4) of reacting a linker precursor B comprising (i) a bioorthogonal reactive group and (ii) a nucleophilic reactive group. The bioorthogonal reactive group (i) and the nucleophilic reactive group (ii) of the second linker unit precursor can be selected from the groups defined above herein with respect to the first linker unit precursor. 【0207】 In this embodiment of step (c-4), the peptide compound of the optical element obtained in step (c-3) reacts with the nucleophilic reactive group of the second linker unit precursor. Specifically, the N-terminus and / or reactive side chains (e.g., lysine side chain, serine side chain, cysteine side chain) of the peptide compound can react with the nucleophilic reactive group of the second linker unit precursor in this embodiment of step (c-4). 【0208】 According to a specific embodiment, the second linker unit precursor has the following structure: 【0209】 【Chemical formula】 has. 【0210】 In step (c-4), an optical element is obtained, the optical element comprising a peptide compound pre-functionalized on at least a part of the surface of the optical element. 【0211】 In a subsequent step (c-5) of the process, the optical element obtained in step (c-4) reacts with a molecular probe or a pre-labeled molecular probe. In step (c-5), a surface-functionalized optical element according to the invention is obtained. 【0212】 According to one embodiment, the process comprises a step (c-5) of reacting the optical element obtained in step (c-4) with a pre-labeled molecular probe. It is preferred that the pre-labeled molecular probe is pre-labeled with a bioorthogonal reactive group suitable for reacting with the bioorthogonal reactive group of the optical element obtained in step (e). Such pairs of bioorthogonal reactive groups are known to those skilled in the art and examples thereof include, but are not limited to, azide / alkyne, azide / strained alkyne, trans-alkene / tetrazene. 【0213】 There are other options for attaching a molecular probe or a pre-labeled molecular probe onto the surface functionalized with the peptide obtained in step (c-3), which can be selected by those skilled in the art. 【0214】 Method for detecting a target analyte In another aspect of the invention, a method for detecting a biomarker is provided. The method comprises (i) contacting a surface-functionalized optical element as defined herein with a suspect sample containing a target analyte, optionally the sample being a human body fluid; (ii) detecting a biomarker based on the interaction between the molecular probe and the target analyte, optionally the interaction between the molecular probe and the target analyte being detected by infrared spectroscopy and optionally the biomarker being based on the band position of amide I of the target analyte. It includes. 【0215】 The sample may be a body fluid, for example, but not limited to, it may be a plasma or cerebrospinal fluid (CSF) sample. According to one embodiment, the sample is a plasma or CSF sample. The sample can be brought into contact with the surface-functionalized optical element in the flow chamber. 【0216】 According to one embodiment, the target analyte can be selected from the group consisting of amyloid beta (Aβ) peptide, alpha-synuclein, tau protein, TDP-43, human islet amyloid polypeptide (hiAPP), prion protein, and p53, and optionally can be selected from the group consisting of amyloid beta (Aβ) peptide, alpha-synuclein, tau protein, and TDP-43. The amyloid beta (Aβ) peptide may be a monomer, oligomer or fibrillar amyloid beta (Aβ) peptide. 【0217】 The interaction between the molecular probe and the target analyte may be detected by any suitable means for detecting biochemical interactions. The interaction may be detected by spectroscopic methods, for example, but not limited to, infrared spectroscopy, UV / Vis spectroscopy, fluorescence spectroscopy, etc. 【0218】 According to one embodiment, the interaction between the molecular probe and the target analyte is detected by infrared spectroscopy, preferably ATR-IR spectroscopy. 【0219】 According to one embodiment, the interaction between the molecular probe and the target analyte is detected by infrared spectroscopy, preferably ATR-IR spectroscopy, in which case the biomarker is the maximum value of the amide band of the target analyte. The band position of amide I may be the maximum value of the amide I band of the amyloid beta peptide, optionally in the range of 1600-1700 cm -1 , optionally in the range of 1620-1670 cm -1 , optionally in the range of 1640-1647 cm -1 within the range. 【0220】 Such methods are known in the art and are described, for example, in Nabers et al, Anal. Chem. 2016, 88, 2755-2762. 【0221】 Use of a surface-functionalized optical element In one aspect, the present invention provides a companion diagnostic test, diagnosing a protein misfolding disease, diabetes or a tumor in a patient, monitoring the therapy of a patient having a protein misfolding disease, diabetes or a tumor, and screening for a drug for the treatment of a protein misfolding disease, diabetes or a tumor using a surface-functionalized optical element according to the present invention or using an optical biosensor according to the present invention for one or more of the foregoing. 【0222】 The protein misfolding disease may be one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's, or prion disease. 【0223】 According to one embodiment, diagnosing Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis in a patient, monitoring the therapy of a patient having Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis, and screening for a drug for the treatment of Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis using a surface-functionalized optical element as defined herein or using an optical biosensor as defined herein for one or more of the foregoing is provided. 【0224】 According to one embodiment, a surface-functionalized optical element or an optical biosensor is used for diagnosing Alzheimer's disease and / or monitoring the therapy of a patient having Alzheimer's disease. 【0225】 In one embodiment, a surface-functionalized optical element as defined herein or an optical biosensor as defined herein is a companion diagnostic test, for diagnosing a protein misfolding disease, diabetes or a tumor in a patient, monitoring the therapy of a patient having a protein misfolding disease, diabetes or a tumor, and screening a drug for treating a protein misfolding disease, diabetes or a tumor and is provided for use in one or more of the foregoing. BRIEF DESCRIPTION OF THE DRAWINGS 【0226】 【Figure 1】 FIG. shows the ATR-FTIR spectra of NHS-functionalized optical elements according to Example 1 (gray: "NHS-PEG-silane") and Comparative Example 1 (black: "NHS-silane") of the invention. 【Figure 2】 FIG. shows the amount of antibody based on the absorbance of Amine II during the stability test of Example 1 (graph including circles: "antibody / / NHS-PEG-silane") and Comparative Example 1 (graph including squares: "antibody / / NHS-silane") of the invention. The figure shows (from left to right): the amount of antibody on the surface in antibody attachment, Wash Step 1 and Wash Step 2. 【Figure 3-1】 FIG. 3A shows a kinetic evaluation of the normalized absorbance of amide II during the stability test described in Example 2C. The figure shows (from left to right): the amount of peptide compound on the surface in peptide attachment, Wash Step 1 and Wash Step 2. 【Figure 3-2】 FIG. 3B shows a kinetic evaluation of the normalized absorbance of amide II during Wash Step 1 described in Example 2C. 【Figure 3-3】 Figure 3C is a diagram showing the ATR-FTIR spectra in the amide I and II regions after the washing step 2 described in Example 2C. 【Figure 4】 It is a diagram showing the normalized ATR-FTIR spectrum of the non-specific protein (NSP) adsorption of BSA described in Example 2D. 【Figure 5】 It is a diagram showing the normalized ATR-FTIR spectrum of the non-specific protein (NSP) adsorption of plasma described in Example 2D. 【Example】 【0227】 Hereinafter, the present invention will be further described by specific examples. The examples should not be understood or construed as limiting the present invention in any way. 【0228】 [Example 1] Surface-functionalized optical element containing a linker construct without a peptide moiety A. Preparation of a surface-functionalized optical element according to an embodiment of the present invention Materials Optical element: Silicon ATR crystal (internal reflection element), trapezoidal, incident angle 45°, 52 mm × 20 mm × 2 mm (Tol: + / -0.1 mm), optically polished Linker I: 1-azido-N-(3-(triethoxysilyl)propyl)-3,6,9,12,15-pentaoxaoctadecane-18-amide Linker II: 2,5-dioxopyrrolidin-1-yl 6-{2-azatricyclo[10.4.0.0 4,9 hexadeca-4,6,8,12,14,16-hexaen-10-yl}-6-oxohexanoate Molecular probe: Anti-β-amyloid (13-28) antibody, mouse monoclonal Device: ATR-IR-biosensor 【0229】 Pretreatment of the silicon crystal The surface was activated by oxidation treatment (plasma treatment) to produce a stable silicon dioxide layer. 【0230】 Silanization of silicon crystals For the silanization of silicon crystals, a solution of linker precursor I in acetone was prepared, and the activated surface of the silicon crystals was coated by contacting the selected surface of the crystals with the silanization solution. The crystals were rinsed with acetone, followed by rinsing with H2O, and then dried under nitrogen. 【0231】 NHS activation of the azide moiety of the silanized surface via SPAAC using linker precursor II The crystal surface pre-silanized with linker precursor I was further reacted with linker precursor II in a SPAAC click reaction to obtain NHS reactivity. As understood by those skilled in the art, the coupling occurs by the reaction of the DBCO group with the azide group on the silanized surface. After the SPAAC click reaction, reactive NHS groups become available on the silanized silicon crystals, which can react with the β-amyloid (13-28) antibody. After the chemical modification of the surface of the silicon crystals with linker precursors I and II was completed, the ATR-FTIR difference spectrum showed NHS ester bands characteristic of 1814, 1783, and 1738 cm -1 (Figure 1, gray spectrum). The combined linker construct from linker precursors I and II is referred to as "NHS-PEG-silane" in Figure 1. 【0232】 Attaching the β-amyloid (13-28) antibody to the NHS-functionalized surface The β-amyloid (13-28) antibody was immobilized in flow under low-salt buffer conditions in a mode applying continuous flow using an ATR-IR biosensor device. During the attachment process, the NHS-activated surface reacted with the primary amine from the antibody, releasing NHS and forming a covalent bond between the surface and the molecular probe. 【0233】 The NHS-functionalized crystal was placed on the crystal holder of the ATR effluent cuvette with the upper (long side) facing up. The lid of the cuvette with a silicone seal inserted was placed on the crystal. The cuvette was placed in the cuvette holder in the IR spectrometer. The sample compartment of the spectrometer was sealed and purged with dry air. The flow system containing the cuvette was flushed with water and then with the attachment buffer. Subsequently, the β-amyloid (13-28) antibody was circulated over the crystal surface. 【0234】 The complete IR spectrum was continuously recorded and compared with the background before antibody attachment. An indicator of the success of antibody immobilization on the surface is the amide 2 signal at 1550 cm -1 (Figure 2, graph "antibody / / NHS-PEG-silane" with circles, part: antibody attachment). 【0235】 B. Preparation of Surface-Functionalized Optical Elements for Comparison Surface-functionalized optical elements for comparison were prepared using a one-step method for preparing the linker construct. A single linker precursor without a poly(alkylene oxide) group was used. 【0236】 Materials Optical element: Silicon ATR crystal (internal reflection element), trapezoidal, incident angle 45°, 52 mm × 20 mm × 2 mm (Tol: + / - 0.1 mm), optically polished Linker precursor III: N-(4,4,4-triethoxysilanebutyl) succinamic acid 2,5-dioxopyrrolidin-1-yl ester Molecular probe: Anti-β-amyloid (13-28) antibody, mouse monoclonal Device: ATR-IR biosensor 【0237】 Pretreatment of Silicon Crystal The surface was activated by oxidation treatment (plasma treatment) to produce a stable silicon dioxide layer. 【0238】 Silanization of Silicon Crystal For the silanization of silicon crystals, a solution of linker precursor III in acetone was prepared, and the activated surface of the silicon crystal was coated by contacting the selected surface of the crystal with the silanization solution. The crystal was rinsed with acetone, followed by rinsing with H2O, and then dried under nitrogen. After the silanization process with linker III was completed, the ATR-FTIR difference spectrum showed NHS ester bands characteristic of 1814, 1783 and 1738 cm -1 (Figure 1, black spectrum). The linker construct obtained from linker precursor III is called "NHS-silane" in Figure 1. 【0239】 Attaching the β-amyloid (13-28) antibody to the NHS-functionalized surface The β-amyloid (13-28) antibody was immobilized in flow under low-salt buffer conditions by applying continuous flow using an ATR-IR biosensor device. During the attachment process, the NHS-activated surface reacted with the primary amine from the antibody, releasing NHS and forming a covalent bond between the surface and the molecular probe. 【0240】 The NHS-functionalized crystal was placed on the crystal holder of the ATR effluent cuvette with the upper (long side) facing up. The lid of the cuvette with a silicone seal inserted was placed on the crystal. The cuvette was placed in the cuvette holder in the IR spectrometer. The sample compartment of the spectrometer was sealed and purged with dry air. The flow system containing the cuvette was flushed with water and then with the attachment buffer. Subsequently, the β-amyloid (13-28) antibody was circulated across the crystal surface. 【0241】 The complete IR spectrum was continuously recorded and compared with the background before antibody attachment. The indicator for the success of antibody immobilization on the surface is the amide 2 signal at 1550 cm -1 (Figure 2, graph "antibody / / NHS-silane" containing squares; part: antibody attachment). 【0242】 C. Stability test The stability test of the molecular probe was carried out on the surface-functionalized optical element of the present invention and on the surface-functionalized optical element for comparison. Two surface-functionalized optical elements were prepared as described above in Examples 1A and 1B. 【0243】 The results are shown in Figure 2, in which the attachment process and washing of the β-amyloid (13-28) antibody are presented in the kinetic profiles of both surfaces. The graph containing circles shown in Figure 2 corresponds to an example according to one embodiment of the present invention in which the spacer portion of the linker construct contains a poly(alkylene oxide) group. The graph containing squares corresponds to a comparative example in which the linker construct does not contain a poly(alkylene oxide) group. After the antibody attachment was completed, the maximum amount of the attached antibody was defined as a comparison for the subsequent washing step by using the maximum value of the absorbance of amide 2 for normalization. Two washing steps were carried out. The first washing step was carried out under low-salt buffer conditions, while high-salt concentration buffer conditions were used in the second washing step. Since the washing spectrum was recorded under the attachment buffer conditions, the artificial effects induced by the washing buffer in the IR spectrum were excluded. 【0244】 The kinetic profiles in this stability test illustrate that a clear difference can be observed between the examples and the comparative examples of the present invention. For the examples of the present invention, a decrease in the amount of the attached antibody could not be monitored. This is shown by the stable profile of the absorbance of amide 2, which represents robust antibody immobilization. 【0245】 In contrast, the comparative examples show a clear loss of the attached antibody in both washing steps. After the first washing step under low-salt buffer conditions, about 90% of the antibody remains, and in the second washing step to which high-salt concentration buffer conditions were applied, the amount of the antibody further decreases to about 80%. 【0246】 When the respective washing spectra in the adhesion buffer were recorded, a stable profile of the absorbance of amide 2 could be observed on both surfaces between the washing steps. This indicates that the comparative examples can be stable in the adhesion buffer. However, the examples of the present invention demonstrate high robustness under all conditions including difficult high-salt concentration buffer conditions. 【0247】 The stability test shows that the use of a spacer portion containing poly(alkylene oxide) improves the stability of the surface-functionalized optical element compared to a linker construct that does not contain poly(alkylene oxide), as demonstrated by the comparative examples. 【0248】 [Example 2] Surface-functionalized optical element comprising a linker construct having a peptide moiety A. Preparation of a surface-functionalized optical element comprising a linker construct having a peptide moiety (linker construct as defined herein) Materials Optical element: Silicon ATR crystal (internal reflection element), trapezoidal, incident angle 45°, 52 mm × 20 mm × 2 mm (Tol: + / -0.1 mm), optically polished Linker precursor I: 1-azido-N-(3-(triethoxysilyl)propyl)-3,6,9,12,15-pentaoxaoctadecane-18-amide Linker precursor II: 2,5-dioxopyrrolidin-1-yl 6-{2-azatricyclo[10.4.0.0 4,9 hexadeca-4,6,8,12,14,16-hexaen-10-in-2-yl}-6-oxohexanoate Peptide compound: Casein fragment blocking solution prepared from bovine casein (Sigma Aldrich / product number: C3400) by alkaline hydrolysis Device: ATR-IR-biosensor 【0249】 Pretreatment, silanization and NHS activation of the silicon crystal The pretreatment, silanization with linker precursor I, and NHS activation with linker precursor II were carried out as described above for Example 1 of the invention. 【0250】 Functionalization of the surface with peptide moieties from a casein-based blocking solution After silanizing the silicon surface and NHS-activating it with linker precursors I and II, protein-reactive silicon crystals were obtained. In the subsequent surface functionalization, the NHS-functionalized crystal surface was further functionalized with peptide moieties from a casein-based blocking solution. Covalent bonds can be achieved via amide bonds between the primary amine groups of lysine in the casein peptide or the N-terminus of the casein peptide and the NHS-functional groups of the silicon crystals. 【0251】 The NHS-functionalized crystals were placed on the crystal holder of the ATR effluent cuvette with the upper (long side) facing up. The lid of the cuvette with a silicone seal was placed on the crystals. The cuvette was placed in the cuvette holder in the IR spectrometer. The sample compartment of the spectrometer was sealed and purged with dry air. The flow system containing the cuvette was flushed with water and then with PBS buffer. Subsequently, the casein fragment blocking solution was circulated over the crystal surface, followed by a washing step with PBS in a flow-through manner. During the functionalization of the surface with peptide moieties, a complete IR spectrum was continuously recorded and referenced against the PBS background. The process was monitored by tracking the increase in the absorbance of amide 2 at 1550 cm -1 over time. Figure 3A (red dots) shows the corresponding kinetic profiles of the attachment and washing of the casein-based peptide solution on the surface of the present invention. 【0252】 Next, the excess NHS groups were quenched with an ethanolamine solution followed by another washing step. 【0253】 The functionalized surface prepared in this Example 2A corresponds to a linker construct containing a peptide moiety as defined herein. The functionalized surface prepared in this example can then be further functionalized with a molecular probe as defined herein, for example, under the above synthetic procedure (B3), steps (c-3) to (c-5) of this specification, or in Example 3 below. 【0254】 B. Preparation of a surface-functionalized optical element for comparison containing a peptide moiety (linker without poly(alkylene oxide) groups) A surface-functionalized optical element for comparison was prepared using a one-step method for preparing a linker construct. A single linker precursor containing no poly(alkylene oxide) groups was used. 【0255】 Materials Optical element: Silicon ATR crystal (internal reflection element), trapezoidal, incident angle 45°, 52 mm × 20 mm × 2 mm (Tol: + / - 0.1 mm), optically polished Linker precursor III: N-(4,4,4-triethoxysilanebutyl) succinamic acid 2,5-dioxopyrrolidin-1-yl ester Peptide compound: Casein fragment blocking solution prepared from bovine casein (Sigma Aldrich / Product number: C3400) by alkaline hydrolysis Device: ATR-IR biosensor 【0256】 Pretreatment and silanization of the silicon crystal The pretreatment and silanization of the silicon crystal were carried out as described in Comparative Example 1 above. 【0257】 Functionalization of the surface with a peptide moiety from a casein-based blocking solution The silicon surface was silanized and NHS-activated with linker B, and a protein-reactive silicon crystal was obtained. In subsequent surface functionalization, the NHS-functionalized crystal surface was further functionalized with a peptide moiety from a casein-based blocking solution. 【0258】 The NHS-functionalized crystal was placed on the crystal holder of the ATR effluent cuvette with the upper (long side) facing up. The lid of the cuvette with the silicone seal inserted was placed on the crystal. The cuvette was placed in the cuvette holder in the IR spectrometer. The sample compartment of the spectrometer was sealed and purged with dry air. The flow system containing the cuvette was flushed with water and then with PBS buffer. Subsequently, the casein fragment blocking solution was circulated over the crystal surface, followed by a washing step with PBS in a flow-through manner. 【0259】 During the functionalization of the surface with the peptide moiety, a complete IR spectrum was continuously recorded and referenced against the PBS background. The process was monitored by tracking the increase in absorbance of amide 2 at 1550 cm -1 Figure 3A shows the corresponding kinetic profiles of the deposition and washing of the casein-based peptide solution on the comparative surface (gray box). 【0260】 Next, the excess NHS groups were quenched with an ethanolamine solution followed by another washing step. 【0261】 C. Stability Test Stability tests were performed on the surface-functionalized optical elements described in Examples 2A and 2B. The results are shown in Figures 3A - 3C. The deposition and washing of the casein-based blocking solution are presented in the kinetic profiles for the functional surfaces of Examples 2A and 2B in Figures 3A and 3B, and additional IR spectra are shown for the second wash in Figure 3C. The functional surface according to Example 2A contains a poly(alkylene oxide) group in the spacer portion of its linker construct and is depicted in the graph containing circles in Figure 3A and is designated as "casein-based blocking solution / / NHS-PEG-silane". The functional surface for comparison according to Example 2B is depicted by the graph containing squares in Figure 3A and is designated as "casein-based blocking solution / / NHS-silane". 【0262】 The attachment process of the casein-derived peptide was carried out for 70 minutes. The functional surfaces according to both Examples 2A and 2B contain a significant amount of attached peptide moieties. However, as can be understood from the data described in FIG. 3A, the functional surface according to Example 2A accumulates approximately 25% more peptide moieties compared to the functional surface according to Example 2B. 【0263】 This result was confirmed in the buffer of the first PBS washing step. In the washing step, the functional surfaces according to Examples 2A and 2B first lose a similar amount of loosely attached peptides. After rinsing the functional surface for 30 minutes, the functional surface according to Example 2A shows approximately 40% more peptides bound to the surface compared to Example 2B. This percentage increase is due to different washing kinetics (FIG. 3B). Since the functional surface according to Example 2A shows a more stable kinetic profile as indicated by the absorbance of stable amide 2, it is demonstrated that it is a more robust peptide-modified linker construct than the functional surface according to Example 2B. 【0264】 The surface stability of the peptide-modified linker construct was further tested in a washing step with a high-salt concentration buffer using 10×PBS buffer solution in a flow-through manner for 10 minutes. Subsequently, the IR spectrum was recorded under normal PBS conditions to avoid buffer-related artifacts in the spectrum (FIG. 3C). Washing with the high-salt concentration buffer demonstrated the improved robustness and stability of the functional surface according to Example 2A compared to Example 2B. No negative absorbance bands were observed in the amide 1 and 2 regions of Example 2A. The effect of the high-salt concentration buffer conditions is different on the functional surface of Example 2B, in which negative amide bands visualized the detachment of the peptide-modified linker construct. 【0265】 The stability tests provided herein for the functional surfaces according to Examples 2A and 2B show that the use of a spacer moiety containing poly(alkylene oxide) improves the stability of the surface-functionalized optical element compared to a linker construct that does not contain poly(alkylene oxide). 【0266】 D. Inactivity Test The functional surfaces prepared according to Examples 2A and 2B were subjected to an inactivity test to demonstrate the sensitivity of the two surfaces regarding non-specific protein (NSP) adsorption. The surfaces were tested for NSP adsorption using bovine serum albumin (BSA) and human plasma. 【0267】 Figure 4 shows the results after circulating BSA for 60 minutes over the functional surfaces prepared according to Examples 2A and 2B respectively, and then washing with 10×PBS in a flow-through manner for another 60 minutes. The functional surface according to Example 2A is referred to as "BSA / / NHS-PEG-silane" (the lower graph in Figures 4 and 5). The functional surface for comparison according to Example 2B is referred to as "BSA / / NHS-silane" (the upper graph in Figures 4 and 5). 【0268】 When the IR spectra were continuously recorded during both steps, significantly improved characteristics regarding NSP adsorption onto the functional surface of Example 2A were elucidated. In the case of BSA, no non-specific attachment onto the functional surface prepared according to Example 2A was observed, whereas there was NSP adsorption of BSA onto the functional surface prepared according to Example 2B. This result was somewhat confirmed when human plasma was circulated for 60 minutes and then washed with 10×PBS in a flow-through manner for another 60 minutes. The results of NSP adsorption after plasma treatment are shown in Figure 5, and a five-fold reduction in NSP adsorption from plasma is demonstrated for the functional surface of Example 2A compared to the surface for comparison of Example 2B. In addition to the position of the maximum value of the amide I band, the overall shape is similar for both surfaces, indicating that there is no difference in the secondary structure distribution of non-specifically bound proteins. 【0269】 The inertness tests provided herein for the functional surfaces according to Examples 2A and 2B show that the use of a spacer portion containing poly(alkylene oxide) improves the inertness against non-specific binding of proteins and human plasma compared to equivalent functionalized surfaces that do not contain such a spacer portion in their linker constructs. The improved inertness can, in turn, improve the detection of target analytes from complex samples. 【0270】 Example 2 further shows that the stability and inertness of the surface-functionalized optical elements according to one embodiment of the present invention are improved, and thus can be advantageously used as part of a biosensor as described herein. 【0271】 [Example 3] A surface-functionalized optical element comprising a linker construct having a peptide portion according to one embodiment of the present invention Materials Optical element: Silicon ATR crystal (internal reflection element), trapezoidal, incident angle 45°, 52 mm × 20 mm × 2 mm (Tol: + / - 0.1 mm), optically polished Linker precursor I: 1-azido-N-(3-(triethoxysilyl)propyl)-3,6,9,12,15-pentaoxaoctadecane-18-amide Matrix precursor compound: 3-(2-(2-methoxyethoxy)ethoxy)-N-(3-(triethoxysilyl)propyl)propanamide Linker precursor II: 2,5-dioxopyrrolidin-1-yl 6-{2-azatricyclo[10.4.0.0 4,9 hexadeca-4,6,8,12,14,16-hexaen-10-yl}-6-oxohexanoate Peptide compound: Casein fragment blocking solution prepared from bovine casein (Sigma Aldrich / Product number: C3400) by alkaline hydrolysis Linker precursor IV: 2,5-dioxopyrrolidin-1-yl 1-{2-azatricyclo[10.4.0.0 4,9{hexadeca-4,6,8,12,14,16-hexaen-10-yn-2-yl}-1,4-dioxo-7,10,13,16,19,22,25,28,31,34,37,40,43-tridecaoxa-3-aza-hexatetracontan-46-oate Linker precursor V: 2,5-dioxopyrrolidin-1-yl 1-azido-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate Molecular probe: Anti-β-amyloid (13-28) antibody, mouse monoclonal Device: ATR-IR biosensor 【0272】 Pretreatment of silicon crystal The surface was activated by oxidation treatment to produce a stable silicon dioxide layer. 【0273】 Silanization of silicon crystal For the silanization of the silicon crystal, a mixture of linker precursor I and matrix precursor compound in 2-propanol was prepared and contacted with the selected surface of the silicon crystal. Subsequently, the crystal was rinsed with H2O and dried under nitrogen. After the silanization was completed, the ATR-FTIR difference spectrum (before and after silanization) showed a band of azide at 2110 cm -1 indicating the azide band. 【0274】 NHS activation of the azide moiety on the silanized surface Linker precursor II was reacted with the pre-silanized crystal surface by SPAAC click reaction. After the completion of the SPAAC click reaction, the ATR-IR difference spectrum (before silanization / after click reaction) showed three NHS bands at 1738 cm -1 1782 cm -1 and 1815 cm -1 . In the difference spectrum, the azide band at 2110 cm -1 disappeared. 【0275】 Production of antibody labeled with azide The anti-amyloid beta antibody was reacted with linker precursor V to prepare an anti-amyloid beta antibody labeled with azide. 【0276】 Surface blocking and antibody immobilization on the blocking layer After silanization and NHS activation by SPAAC click reaction, protein-reactive silicon crystals were obtained. In subsequent surface functionalization, the NHS-functionalized crystal surface was first blocked with a casein fragment solution. The NHS-functionalized crystals were placed on the crystal holder of the ATR effluent cuvette with the upper (long side) facing up. The lid of the cuvette with a silicone seal inserted was placed on the crystal. The cuvette was placed in the cuvette holder in the IR spectrometer. The sample compartment of the spectrometer was sealed and purged with dry air. The flow system containing the cuvette was flushed with water and then with PBS buffer. Subsequently, the casein fragment blocking solution was circulated over the crystal surface, followed by a washing step with PBS in a flow-through manner. During the blocking process, a complete IR spectrum was continuously recorded and referenced against the PBS background. The blocking process was monitored by following the increase in the absorbance of amide 2 (1550 cm-1) and simultaneously the decrease in the NHS absorbance (1740 cm -1 ). Next, the excess NHS groups were quenched with an ethanolamine solution followed by another washing step. 【0277】 Subsequently, the peptide blocking layer was functionalized with DBCO by reacting it with linker precursor III containing NHS and DBCO in a flow-through manner. 【0278】 In the next step, the pre-prepared anti-amyloid beta antibody labeled with azide was immobilized on the peptide blocking layer functionalized with DBCO by a SPAAC click reaction between the flow-through DBCO moiety and the azide group. During antibody attachment, a complete IR spectrum was continuously recorded and compared with the background before antibody attachment. The indicator of the success of antibody immobilization on the surface is the amide 2 signal (1550 cm-1).

Claims

[Claim 1] An optical element with a surface functionalized surface, including an IR-transmitting optical element, At least a portion of the surface of the IR-transmitting optical element is bonded to a molecular probe by a linker structure. The aforementioned linker structure, Surface adhesion portion, and Spacer portion containing poly(alkylene oxide) Optical elements with surface functionalization, including those mentioned above. [Claim 2] The surface-functionalized optical element according to claim 1, wherein the IR-transmitting optical element is an attenuated total reflection infrared (ATR-IR) waveguide. [Claim 3] The surface-functionalized optical element according to claim 1 or 2, wherein at least a portion of the IR-transmitting optical element has an oxide surface layer, and at least a portion of the oxide surface layer is covalently bonded to the linker structure. [Claim 4] The surface-functionalized optical element according to claim 1 or 2, wherein the linker structure covalently bonds the molecular probe to the surface of the IR-transmitting optical element. [Claim 5] The surface-functionalized optical element according to claim 1 or 2, wherein the spacer portion contains a ligation group obtainable by a bio-orthogonal ligation reaction. [Claim 6] The surface-functionalized optical element according to claim 1 or 2, wherein the poly(alkylene oxide) which is part of the spacer portion is polyethylene glycol. [Claim 7] The aforementioned linker structure is given by formula (A): / / -(S)-(SP)-\\ (A) It has a structure that follows, During the ceremony, / / indicates adhesion to the surface of the IR-transmitting optical element, (S) represents the surface attachment portion, (SP) represents the spacer portion, \\ represents attachment to another part of the linker structure or to the molecular probe, The aforementioned surface-adhering portion (S) is given by formula (S-I): / / -Y １ -8 １ -8 １ -$$ １ (S-I) It has a structure that follows, During the ceremony, / / indicates adhesion to the surface of the IR-transmitting optical element, Y １ is -O-Si(R １ ) ２ -, and R １ is independently selected from H, OH, optionally substituted alkyl, optionally substituted alkoxy, -O- / / , and -O-Si ｘ , and Si ｘ is a silicon atom of a surface - attached moiety containing another silicon, or is a silicon atom of a matrix silane attached to the surface of the optional IR - transmitting optical element. L １ This is an optional unit of connection, X １ is a group selected from -C(O)NH-, -NHC(O)-, -NHC(O)HN-, and -NHC(O)O-. $$ １ The surface-functionalized optical element according to claim 1 or 2, wherein the element is attached to the spacer portion. [Claim 8] The aforementioned linker structure is given by formula (A): / / -(S)-(SP)-\\ (A) It has a structure that follows, During the ceremony, / / indicates adhesion to the surface of the IR-transmitting optical element, (S) represents the surface attachment portion, (SP) represents the spacer portion, \\ represents attachment to another part of the linker structure or to the molecular probe, The aforementioned spacer portion (SP) is given by equation (SP-II) $$ ２ -L ２ -X ２ -L ３ -H １ -L ４ -§§ １ (SP-II) It has a structure that follows, During the ceremony, $$ ２ This represents adhesion to the surface adhesion portion (S), L ２ ~L ４ Each of these is an independent, arbitrarily chosen unit of connection. X ２ is, -(OCH ２ CH ２ )n １ - and n1 is an integer between 2 and 100. H １ is of formulas (HET-I) to (HET-VI): 【Chemistry 1】 An N-heterocyclic group having a structure that follows any one of the following, which may be optionally substituted: && １ is, L ３ It represents adhesion to, or L ３ If X does not exist, ２ In response to, && ２ is, L ４ It represents adhesion to, or L ４ If it does not exist, §§ １ In response to, R ＊ is H, an optionally substituted alkyl group, or an optionally substituted aryl group, Ring A is an optionally substituted eight-membered carbocyclic compound or an optionally substituted eight-membered heterocycle; §§ １ The surface-functionalized optical element according to claim 1 or 2, wherein is an attachment to another part of the linker structure or to the molecular probe. [Claim 9] The linker construct includes a peptide portion that covalently bonds the spacer portion and the molecular probe, The aforementioned linker structure is given by formula (B): / / -(S)-(SP)-(Pep)-\\ (B) It has a structure that follows, During the ceremony, / / indicates adhesion to the surface of the IR-transmitting optical element, (S) represents the surface attachment portion, (SP) represents the spacer portion, (PEP) is the peptide portion, \\ represents attachment to the molecular probe, The peptide portion (Pep) is defined by formula (PEP-I): §§ ２ -P １ -L ５ -H ２ -L ６ -## １ (PEP-I) It has a structure that follows, During the ceremony, §§ ２ This indicates adhesion to the spacer portion (SP), P １ This is a peptide compound selected from the group consisting of peptides, proteins, and protein fragments, and each of these may be optionally substituted. L ５ and L ６ Each of these is an independent, arbitrarily chosen unit of connection. H ２ The equations are (HET-VII) to (HET-XII): 【Chemistry 2】 An N-heterocyclic group having a structure that follows any one of the following, which may be optionally substituted: %% １ is, L ５ It represents adhesion to, or L ５ If P does not exist, １ In response to, %% ２ is, L ６ It represents adhesion to, or L ６ If it does not exist, # １ In response to, R ＊＊ is H, an optionally substituted alkyl group, or an optionally substituted aryl group, Ring B is an optionally substituted eight-membered carbocyclic compound or an optionally substituted eight-membered heterocycle; ## １ The surface-functionalized optical element according to claim 1 or 2, wherein the element represents adhesion to the molecular probe. [Claim 10] The surface-functionalized optical element according to claim 1 or 2, wherein the molecular probe is an antigen, antibody, antibody fragment, antibody fusion protein or fusion protein with an antibody fragment, antibody conjugate or conjugate with an antibody fragment, optionally a protein complex containing an antibody fragment or its fusion protein, antikalin, nanobody, small organic molecule, drug, nucleic acid, aptamer, lipid, carbohydrate, or peptide, and / or the molecular probe is capable of forming a complex with a protein associated with protein misfolding disease. [Claim 11] At least a portion of the surface of the IR-transmitting optical element is defined by formula (MA-a): / / -(S)-(PAO spacer)-(cap) (MA-a) It is covalently bonded to a matrix silane having a structure that follows the following: During the ceremony, " / / " indicates adhesion to the surface of the IR-transmitting optical element, (S) represents the surface attachment portion, (PAO spacer) refers to the spacer portion containing a poly(alkylene oxide) group. (cap) represents an inert end group, the surface-functionalized optical element according to claim 1 or 2. [Claim 12] An optical biosensor comprising a surface-functionalized optical element as described in claim 1. [Claim 13] A method for preparing a surface-functionalized optical element according to claim 1 or 2, (a) A step of providing an IR-transmitting optical element, (b) A step of reacting at least a portion of the surface of the IR-transmitting optical element with a compound containing poly(alkylene oxide). Methods that include... [Claim 14] A method for detecting biomarkers, (i) A step of bringing a surface-functionalized optical element according to claim 1 or 2 into contact with a sample suspected to contain a target analyte, wherein the sample is optionally a human bodily fluid; (ii) A step of detecting the biomarker based on the interaction between the molecular probe and the target analyte, wherein optionally the interaction between the molecular probe and the target analyte is detected by infrared spectroscopy, and optionally the biomarker is based on the band position of amide I of the target analyte. Methods that include... [Claim 15] Companion diagnostic test, To diagnose protein misfolding disorders, diabetes, or tumors in patients, Monitoring the therapy of patients with protein misfolding disorders, diabetes, or tumors, and Screening for drugs to treat protein misfolding disorders, diabetes, or tumors. Use of one or more of the surface-functionalized optical elements according to claim 1 or the optical biosensor according to claim 12.

Images