Screening assays, modulators, and modulators for activation of the advanced glycation end product receptor (RAGE).

Abstract

To provide pharmaceutical compositions for treating, preventing or managing RAGE-related disorders.SOLUTION: The invention provides: an isolated or purified peptide which comprises an amino acid sequence represented by a specific sequence and inhibits RAGE ligand-independent signaling; a fused polypeptide comprising the peptide; a nucleic acid comprising a nucleotide sequence that encodes the peptide or fused polypeptide; and a pharmaceutical composition comprising the peptide, fused polypeptide or nucleic acid. The pharmaceutical composition is used for treating, preventing or managing a RAGE-related disorder in a patient in need of the treatment, prevention or management.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention generally relates to the modulation of receptor activation associated with specific diseases and / or conditions. Screening assays for identifying modulators, such modulators, such The present invention relates to a treatment method including the administration of a modulator. More specifically, the present invention relates to S100A 8 / A9, RAG by RAGE ligands containing advanced glycation end products (AGEs) and HMGB1 Activated type 1 angiotensin receptor (AT1R), with or without regulation of E activation. and certain co-existing activated G proteins, including activated CC chemokine receptor 2 (CCR2). RAGE ligand-independent mechanism by coupled receptor (GPCR) (RAGE (R) Advanced Glycation End Product Receptor (R) via E-ligand-independent transactivation (also known as E-ligand-independent transactivation) The present invention relates to a modulator for the activation of AGEs. Screening assays for determining RAGE-related disorders using the modulator This also concerns methods for dealing with the damage. [Background technology]

[0002] Advanced glycation end product receptors (RAGE) belong to the immunoglobulin (Ig) superfamily. It is a polyvalent type I transmembrane glycoprotein (Neeper et al., 1992). 5 Glycosylated RAGE proteins with a range of 0-55 kDa are found in a limited range of cells (e.g., blood). RAGE expression is constitutively expressed in vascular endothelium, type II lung cells, and leukocytes, but RAGE expression is associated with injury and inflammation. It can be induced in most cell types and tissues after the disease (Ballinger et al., 2020). 05). RAGE expression is associated with cardiovascular disease (CVD), cancer, diabetes, and chronic kidney disease (CKD). Important inflammatory and synovial diseases, including but not limited to ischemic injury and Alzheimer's disease. It is significantly upregulated in psychosomatic disorders (Yan et al., 2010).

[0003] Genetic deletion of the AGER gene, which encodes RAGE, is associated with several cancers (Malik et al., 2015) and inflammation including atherosclerosis and diabetic complications Numerous diseases and conditions in mice, including the disease (Chuah et al., 2013). It has been previously demonstrated that it provides protection from the disease process. For example, apolipotampa In chlorite E (apoE) knockout (KO) mice, the deletion of RAGE leads to aging As plaque buildup decreases, atherosclerosis accelerated by diabetes is reduced. Reduced (Soro-Paavonen et al., 2008). Similarly, AGE R deletion reduces renal impairment in diabetic mice without affecting glucose regulation. It is possible (Thomas et al., 2005).

[0004] AGER gene polymorphisms are associated with arthritis, atherosclerosis, diabetic complications, and cancer. This includes, but is not limited to, risks of obesity, epilepsy, and cognitive impairment, including Alzheimer's disease. It has been associated with numerous undefined diseases and disease processes in humans.

[0005] Advanced glycation end products (AGEs) and non-AGE ligands (protein S100 glycanulates) RAG by members of the family, including HMGB1, amyloid and Mac-1 The binding of E to the extracellular domain is linked to the nuclear factor kappa B (NFκB) and renin-angiotenoids. The rheumatoid arthritis system (RAAS), including the rheumatoid arthritis system (RAAS), is involved in inflammation, injury, and dysfunction. It activates a chain of signal transduction cascades.

[0006] In the experimental model, the ligand-mediated activation of RAGE was inhibited using a soluble decoy receptor. The harm is reduced by attenuating atheroma formation and vascular damage (Schmidt et al. 1999). This is because the pathological effects of RAGE are ligand-mediated in such a setting. This means that it is partially mediated by activation.

[0007] The exact molecular mechanism by which RAGE is activated and all its biological effects are as follows: These clinically important signaling pathways are not well understood, and therefore, targeting them is difficult. The ability to do so has yet to be found in clinical settings.

[0008] The renin-angiotensin-aldosterone system (RAAS) is involved in many common diseases. It is an important homeostatic pathway involved in the onset and progression of the disease process. Otensin-converting enzyme (ACE) inhibitors or angiotensin II receptor type 1 (AT1R) Renin-angiotensin-aldosterone system (RAA) blockers (inhibitors) Inhibition of S) is associated with hypertension, cardiovascular disease (CVD), heart failure, chronic kidney disease (CKD), and diabetes. It is widely used in the management of many diseases and / or conditions, including pathological complications. RAAS inhibition This includes the prevention of diabetes (Tikellis et al., 2004) and neuroprotection (Thoe (Shen-Reineke et al., 2011), mitigation of growth in certain cancers (Shen et al., 2016) and by deleting the AT1R gene, which gives mice a longer lifespan. It has also been shown to have advantages in aging (Benigni et al., 2009). It is being done.

[0009] These effects of RAAS blockers are related to the blood pressure reduction induced by RAAS blockers. It is added below and independent of it. This means that it does not lower blood pressure to the same extent as other drugs. This is because it does not provide the same advantages (Lee et al., 1993). In particular, Angio Activation of AT1R by tensin II (Ang II) is a pathway that causes vasoconstriction. Induction of oxidative stress, activation of nuclear factor κB (NFκB), and inflammation occur through different pathways. To wake up.

[0010] Activation of the renin-angiotensin-aldosterone system (RAAS) is a major factor in atherosclerosis. It is known to be an important mediator of muscular arteriosclerosis (Lee et al.). ,1993; and Jacoby et al.,2003). Atheroma formation is, Otensin (Ang) II increases after infusion, and in experimental models, its effect on blood pressure homeostasis. Independently of the effect, a low-salt diet (Tikellis et al., 2012), diabetes (G ldin et al., 2006; and Soro-Paavonen et al., 2008) and genetic deletion of angiotensin-converting enzyme 2 (Ace2) (Thomas It is related to physiological RAAS activation, including et al., 2010. Similarly, RAAS Inhibition of this process is in addition to lowering systemic blood pressure, and also has an independent anti-atherosclerotic effect. Having a use (Candido et al., 2002; Candido et al. ,2004; and Knowles et al.,2000). Ang II is an oxide. Tres induction (Rajagopalan et al., 1996), vascular adhesion (Gra fe et al., 1997) and inflammation (Marvar et al., 2010) It has numerous direct atherosclerotic-promoting effects (Daugherty et al.) al., 2000; Ferrario et al., 2006; and Ekholm et al., 2009).

[0011] These atherosclerotic-promoting effects are mainly due to the type 1 angiotensin receptor (AT1 Activation of R) and subsequent induction of reactive oxygen species (ROS) and NFκB signaling It is thought to be mediated by activation (Li et al., 2008). However, However, this includes relative independence from conventional vasoconstrictive signaling mediated by AT1R. The signal transduction mechanisms underlying these effects are not fully understood.

[0012] Furthermore, specific chemokine signaling pathways are involved in the pathogenesis of atherosclerosis. The study also showed that macrophage infiltration into arterial lesions directly contributes to this abnormal type of inflammatory disease. (Boisvert et al., 2004). In fact, all known CCs and The CXC chemokine receptor, as well as CX3CR1 and XCR1, are associated with inflammation. (Murphy et al. 2000; Zlotnik and Yoshie 2) 000). The primary physiological function of chemokine ligands (CCLs) is "regular immune surveillance." It regulates inflammation and cell migration during development. (Allen et al., 2007) CCL is released in response to pro-inflammatory cytokines and has physiological effects on chemokines. It selectively binds to a large family of G protein-coupled receptors that mediate responses. Cytokines were originally called chemotactic cytokines.

[0013] Animal model studies of chronic inflammatory diseases involve antagonists and MCP-1 (monocyte chemotaxis). Protein 1, also known as monocyte chemoattractant protein 1, monocyte chemotaxis and activator (MCAF) Furthermore, chemokine (CC motif) ligand 2 (CCL2) and CCR2 (chemokine We demonstrated that inhibiting the binding between (CC motif) receptor 2) suppresses the inflammatory response. The interaction between MCP-1 and its recognition receptor CCR2 is related to uveitis, atherosclerosis. Arteriosclerosis, rheumatoid arthritis, multiple sclerosis, Crohn's disease, nephritis, organ transplant rejection, lung Fibrosis, renal failure, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic Retinitis, diabetic microangiopathy, tuberculosis, sarcoidosis, invasive staphylococcal infection, cataracts Post-operative inflammation, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma Breath, periodontal disease, periodontitis, gingivitis, gingival disease, diastolic cardiomyopathy, myocardial infarction, myocarditis, chronic heart failure Vascular stenosis, restenosis, reperfusion injury, glomerulonephritis, solid tumors and cancer, chronic lymphocytic leukemia Chronic myeloid leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and bladder, breast, and cervix. It is associated with the pathological conditions of inflammatory diseases such as cancers of the sphincter, colon, lung, prostate, or stomach (Ro llins, 1996; Dawson et al., 2003).

[0014] MCP-1 and CCR2 knockout mice exhibit the absence of these signaling pathways. This demonstrates a significant reduction in monocyte infiltration into inflammatory lesions. Furthermore, such K O mice are used to treat experimental allergic encephalomyelitis (EAE, a model of human multiple sclerosis), cockroaches It is resistant to the development of briar allergen-induced asthma, atherosclerosis, and uveitis. Patients with rheumatoid arthritis and Crohn's disease exhibit decreased MCP-1 expression and reduced number of infiltrating macrophages. TNFα antagonists at dose levels correlated with (e.g., monoclonal antibodies and others) The condition improved during treatment with soluble receptors.

[0015] MCP-1 is associated with the pathogenesis of seasonal and chronic allergic rhinitis, and Chilid It has been found in the nasal mucosa of the majority of patients with allergies. MCP-1 is in vitro It has also been found that this induces histamine release from basophils. During an allergic state, Both allergens and histamine are present in the nasal mucosa of people with allergic rhinitis. It has been shown to induce (i.e., upregulate) the expression of -1 and other chemokines. Therefore, this suggests the existence of a positive feedback loop in such patients. Yes, they are.

[0016] Kidney disease is associated with chronic inflammation characterized by the accumulation of renal macrophages. The production of monocyte chemoattractant protein 1 (MCP-1 / CCL2) by diabetic nephropathy It has been identified as a major factor influencing macrophage accumulation in kidney disease. (Tesch et al., 2008). Inhibition of CCR2 in various animal models. , and / or inhibition of a specific CCR2 pathway, and / or inhibition of the CCR2 ligand MCP-1 It has been shown to reduce kidney damage (Tesch et al., 2008; Rao V et a.,2006;Kang et al.,2010;Kitagawa et al., 2004; Park J et al., 2008).

[0017] Tesch (2008) showed that selective targeting of MCP-1 is effective in treating kidney diseases, including diabetic nephropathy. It is noteworthy that this has been proven to be an effective treatment in suppressing the condition in animal models. R2 small molecule antagonist (INCB3344, propagermanium, RS-5043) Treatments including 93) have been shown in mouse models to treat multiple sclerosis, renal ischemia-reperfusion injury, ureteral obstruction, and glucose. It has been shown to suppress inflammation in urinary nephropathy and arthritis in rat models. CCR2 Artificial biological antagonists have also proven effective. MCP-1 deficiency Subcutaneous injection of cells transduced with an inactive vector is used to treat lupus nephritis in mice. Dell has been found to suppress the development of kidney inflammation. Similarly, 7ND (MCP-1 mutation) Muscle transduction by heterologous organisms is associated with renal ischemia-reperfusion injury, lupus nephritis, and diabetic nephropathy. To reduce renal inflammation in the inflammatory model. To date, chemokine monotherapy for inflammatory diseases. Human trials have not led to drug approval. Anders HJ et al. have shown that a single chemokine We investigated why antagonist treatment was ineffective in treating the disease, and single chemokines We discuss possible explanations, including the redundancy of the deator and the variable expression patterns of chemokine receptors. (Anders HJ et al. 2010). Therefore, the CCR2 pathway There is a technical need for effective treatment of diseases caused by activation.

[0018] The subject of this invention is the activation of RAGE via coexisting GPCRs, which act as RAGE ligands. The concept that they can be activated independently is relevant to many GPCRs, particularly those associated with inflammation and cell proliferation. It is important to note that this is meaningful for GPCRs.

[0019] RA between certain activated coexisting GPCRs, including AT1R and CCR2, and RAGE Novel functional interactions independent of GE ligands are explained despite the underlying technology. That is the case. [Overview of the project] [Problems that the invention aims to solve]

[0020] RAGE signaling, Renin-Angiotensin-Aldosterone System (RAAS) And certain chemokine signaling pathways are involved in the development and progression of vascular complications. Functional interactions are known. For example, the binding of RAGE ligands to RAGE. This can induce pro-inflammatory signaling, which is the antagonist of AT1R. It can be reduced by (inhibitors) (for example, Fukami et al. 2 004). Similarly, activation of the AT1R receptor by Ang II is associated with the RAGE ligand. Increases formation and release, inhibits RAGE ligand binding to RAGE or RAGE ligand Interventions that reduce the risk can attenuate Ang II-AT1R-induced injury. For example, Thomas et al. 2005). RAGE activation by RAGE ligands. Some downstream signaling pathways and mediators induced after sexualization, particularly those that cause inflammation. This is induced after Ang II-mediated activation of AT1R (e.g., NFκB activation). It is also similar to the signaling pathways and mediators involved.

[0021] This prior art involves RAGE and angiotensin receptors such as AT1R or CCR2. No evidence or disclosure is provided regarding the formation of complexes with any specific chemokine receptor or other GPCRs. It has not been done. Also, this does not affect the angiotensin receptor or MCP by Ang II. Activation of coexisting GPCRs by GPCR recognition ligands such as CCR2 via -1 is RA This could also directly lead to the activation of the cytoplasmic tail of GE, particularly RAGE. In the absence of a RAGE ligand, or the RAGE ligand-binding external domain of RAGE. It is also expected that subsequent signal transduction via RAGE will not actually require its presence. This is not the case. Therefore, it does not regulate ligand-independent activation of the cytoplasmic tail of RAGE. This includes the binding of Ang II to AT1R or the binding of MCP-1 to CCR2, etc. This likely involves the regulation of signal transduction induced after the activation of specific coexisting GPCRs. That was something I never expected.

[0022] One of the notable features of RAGE is its single ligand and single binding site, which are susceptible to inhibition. Rather, it is activation by multiple ligands at multiple sites on the external domain. RAGE is Advanced glycation end products (AGEs) and high mobility group box 1 (HMGB-1), S-100 / C Lugranulin, SAA, Aβ, C3a, Heat Shock Protein 70 (HSP70) , a progenitor cell injury-related glycoprotein, an acidic and cysteine-rich secreted protein (SPARC ), β2-integrin Mac-1 (CD11b), phosphatidylserine (PS), two Single-stranded DNA (dsDNA), double-stranded RNA (dsRNA), lipopolysaccharide (LPS), and tannins. It can be activated by other non-AGE ligands, including protein peroxides.

[0023] Activation of the extracellular domain of RAGE by RAGE ligand is linked to NFκB activation and This leads to subsequent inflammation, oxidative stress, fibrosis, and cell proliferation, resulting in the development of NFκB-driven genes. It causes the present (Bierhaus et al., 2001).

[0024] RAGE ligand-induced signaling involves RAGE ligand-receptor interactions and NFκ This also triggers a positive feedback loop that increases RAGE expression via B activation. This enhances subsequent RAGE-induced cell activation. In fact, the inventors of this invention have found that RA The only known way to strongly downregulate GE expression is to reduce RAGE activation. This is the situation where, as ligand levels increase, receptor expression decreases. This is in contrast to other receptors such as the lipoprotein (LDL) receptor.

[0025] Importantly, the inventors have developed a method for AT1R by Ang II or CC by MCP-1. After activation of specific coexisting GPCRs such as R2, any RAGE ligand or RAGE molecule Independent of the extracellular domain, the cytoplasmic tail of RAGE is activated, leading to inflammation and oxidative stress. Activity of NFκB, an important transcription factor involved in cell regeneration, fibrillation, cell proliferation, and cell survival. This demonstrated the initiation of downstream signaling that leads to transformation. The absence of RAGE expression, and specific... The absence of expression of key domains in the cytoplasmic tail of RAGE is a sign of the finer points of RAGE. Independent of extracellular domain expression, Ang II-mediated AT1R or MCP-1-mediated C It prevents the induction of NFκB activation after activation of coexisting GPCRs such as CR2. Although we do not wish this to happen, the inventors have identified certain coexistences including AT1R and CCR2. RAGE ligand-independent activation of the cytoplasmic tail of RAGE by activated GPCRs We consider this to be the dominant pathway for activating RAGE. Furthermore, we are once again constrained by theory. Although not our intention, the inventors have found that, for example, a fine-grained organism exposed to injury, stress, or hypoxia can be used to treat small tissues. De novo expression of RAGE in cells activates established GPCR signaling via We believe it provides a conduit for the pro-inflammatory signaling that occurs.

[0026] The inventors have identified specific methods such as AT1R by Ang II or CCR2 by MCP-1. RAGE ligand-independent activity of the cytoplasmic tail of RAGE after activation of coexisting GPCRs This also demonstrated that the compound triggers signaling that increases RAGE expression.

[0027] RAGE is related to many aspects of tumor biology, including tumor cell proliferation, migration, and invasion. (Malik et al., 2015; Abe et al., 2008) Many cancers have higher levels of RAGE (for example, breast cancer, colon cancer, There is kidney cancer and gastric cancer (Taguchi et al., 2000). RAGE is, RAGE expression is a normal part of lung function, and is lost when lung cells differentiate and become malignant. Lung cancer in which this decreases is an exception (Marinakis et al., 2014). 6. In glioma cells, tumor volume is significantly higher in tumors composed of cells where RAGE is blocked. It decreases rapidly. In contrast, tumors that overexpress RAGE grow rapidly and affect the surrounding tissue. It infiltrated very efficiently (Taguchi et al., 2000). As a cancer treatment. The demand for therapeutic agents to block RAGE signaling in polymorphic glioma / medulloblastoma (Ta guchi et al., 2000; Pancreatic cancer (Malik et al., 201 5;Leclerc et al.,2015);Melanoma(Malik et al., 2015); Prostate cancer (Malik et al., 2015); Breast cancer (Malik et al., 2015); Liver cancer (Logsdon et al., 2015) 07; Volz et al., 2010); and colon cancer (Sparvero et al.) This includes, but is not limited to, those cancers, including al., 2009. It has come.

[0028] Preclinical and clinical studies support the possibility that RAGE inhibitors may be useful in treating this condition. RAGE is associated with a wide range of brain disorders, including but not limited to Alzheimer's disease. (Cai et al., 2016). Other brain processes involved in RAGE signaling Conditions include amyotrophic lateral sclerosis (Ray et al 2016); Huntington's disease (R Ray et al 2016); Creutzfeldt-Jakob disease (Ray et al 2 016); Diabetic neuropathy, familial amyloid polyneuropathy, Charcot neuroarthritis and neurodegenerative conditions such as vasculitic neuropathy (Ray et al 2016); neuropathy Pain (Wan et al., 2016); Development and progression of glioma (Angelop oulou et al., 2016); and ischemic brain injury / stroke (Xia et al. This includes, but is not limited to, those cited in al. 2010.

[0029] In a healthy state, RAGE expression in the lungs is the highest of all tissues. However, RAGE expression in the lung is usually found only in type 1 lung cells. Upregulation of RAGE signaling in certain areas is associated with chronic obstructive pulmonary disease (COPD) / pulmonary pulmonary disease. tumors (Sukkar et al., 2012); asthma (Sukkar et al., 2 012); Injuries due to smoking / contamination; Acute lung injury / Acute respiratory distress syndrome (ARDS) (Gu o et al., 2012); and broad lung diseases including, but not limited to, pulmonary fibrosis. It has been associated with disability.

[0030] RAGE is critically involved in many inflammatory diseases, and as a result, its treatment is a potential therapeutic factor. It becomes a target. Such conditions include inflammatory arthritis (Sparvero et al.,2 009; Chuah et al., 2013); Osteoarthritis (Xie et al. ,2013); Retinal diseases (Barile et al.,2007); Atherosclerotic arteries sclerosis (Soro-Paavonen et al., 2008; Schmidt et al. al.,1999;Park et al.,1998;Zhou et al.,2 003;Yan et al.,2010);vascular calcification(Ott et al.,20 14); Cardiomyopathy (Volz et al., 2010; Russo et al., 20 16); Ischemic heart disease / cardiac remodeling / fibrosis (Yan et al., 2010; Ramasamy et al., 2012); heart failure (Ramasamy et al. .,2012); Diabetic and non-diabetic kidney disease (Fukami et al.,201 5; Gugliucci et al., 2014); Inflammatory bowel disease (Ott et al. l., 2014); Pre-eclampsia (Daffu et al., 2013); Polycystic ovary syndrome Symptoms (Garg et al., 2015): Steroid hepatopathy, fibrosis, ischemic and non-ischemic hepatopathy Injury (Yamagishi et al., 2015); Spinal cord injury (Yamagishi et al., 2015; Skin inflammation and aging (Tong et al., 2014) This includes, but is not limited to, ; and keratitis (Tong et al., 2014). I can't. [Means for solving the problem]

[0031] This invention relates to RAGE, which, together with specific coexisting GPCRs including AT1R and CCR2, in the cell membrane. Partially resulting from our determination that it forms a receptor heteromer complex within it. .

[0032] Furthermore, the present invention relates to an angiotensin receptor in the form of AT1R (in this case, Ang I (by I) or specific chemokine receptors such as CCR2 (in this case, by MCP-1) Activation of certain coexisting GPCRs is RAGE ligand-independent of the cytoplasmic tail of RAGE. This arises in part from the inventors' recognition that it causes cellular activation.

[0033] The inventors have identified specific methods such as AT1R by Ang II or CCR2 by MCP-1. The activation of coexisting GPCRs is via a common mechanism that leads to the domain of the cytoplasmic tail of RAGE. This demonstrated that it leads to the activation of the RAGE ligand. This pathway of transactivation is the RAGE ligand It does not require release, or does not require binding to the extracellular domain of RAGE (that is, This is RAGE ligand-independent RAGE activation.

[0034] There is publicly available data suggesting that the cytoplasmic tail of RAGE is phosphorylated. However (Sakaguchi et al., 2011), the present inventors have found that Ang II RAGE ligands are induced after activation of specific coexisting GPCRs, such as the AT1R receptor. Independent signaling is transmitted when the cytoplasmic tail of RAGE is serine 391 or RAGE is transmitted through cells. This demonstrated that phosphorylation at other parts of the quality tail is not required. Furthermore, this development The researchers found that there are no RAGE homologs from other mammals or any residues that can maintain phosphorylation. RAGE mutants that do not exhibit ligand-dependent activation of RAGE and RAGE ligand-independent activation also exhibit ligand-dependent activation of RAGE. Because it is activated in response to sexual activation and can induce signal transduction, RAG After binding of a RAGE ligand (e.g., S100A8 / A9) to the extracellular domain of E The induced RAGE ligand-dependent signaling is such that the cytoplasmic tail is serine 391 or It does not necessarily require phosphorylation at other sites on the cytoplasmic tail of RAGE. It was also shown that there are no N-terminal truncated constructs of RAGE (e.g., S39). 1A-RAGE 362-404 The inhibitory function of ) is the absence of the RAGE phosphorylation target. This is maintained even below, thereby achieving the modulating effect of the RAGE structure described by the inventors. It was confirmed that this is independent of RAGE phosphorylation.

[0035] Conventional technologies involve inhibitors of PKCζ that are RAGE-mediated and RAGE ligand-dependent (for example) It inhibits (s100-inducible) signaling and many other PKCζ-dependent pathways. It has been proven that in humans and animals, genetic deletion of PKCζ leads to serious diseases. The researchers have shown that inhibitors of PKCζ are RAGE ligand-independent via full-length RAGE (i.e., It was also shown that it inhibits trans-activation-induced signaling. However, RAG N-terminal truncated constructs of E (e.g., RAGE)362-404 The adjustment function of P Unaffected by KCζ inhibition, thereby the RAGE structure described by the inventors It is confirmed that the regulatory effect of the structure does not depend on PKCζ.

[0036] Inhibitors of the shared pathway induced following RAGE activation (e.g., myD88, TIRA) P, interleukin-1 receptor-related kinase 4 (IRAK4 or NFκB) is RA GE ligand-dependent (e.g., s100-inducible) and RAGE ligand-independent (i.e., It nonspecifically blocks both RAGE-mediated signaling (trans-activation-inducible). Other receptors (e.g., TLRs) also use these signaling molecules / pathways, therefore Inhibition of any of these mediators is not specific to RAGE signaling, These signaling mediators affect many other functions, which in turn affects human health. Potentially harmful to (e.g., genes such as myD88, TIRAP, IRAK4, or NFκB) Unlike RAGE deletions, this deletion is harmful to humans and animals.

[0037] The inventors further developed selective tuning, such as inhibition of RAGE ligand-independent signaling. The section selectively targets signaling via the cytoplasmic tail of RAGE. This demonstrates that this can be achieved, and the inventors' assay and the modulators identified therefrom. However, this transactivation (RAGE ligand-independent RAGE activation) process is affected It was shown that it would be done.

[0038] The present inventors further developed RAGE ligand-dependent activation and RAGE signaling Dual inhibition of RAGE ligand-independent transactivation of signaling is also possible, as is the cytoplasmic side of RAGE. We demonstrated that this can be achieved by selectively targeting signal transduction mediated by the signaling pathway. The inventors' assay and the modulators identified therefrom are shared mediators This demonstrated that it can act simultaneously on both methods of RAGE activation. , soluble RAGE 22-331 Selected RAGE neutralizing antibody and RAGE extracellular domain Low-level molecules that may bind to RAGE and inhibit only RAGE ligand-dependent activation of RAGE. They are directly distinguished from children.

[0039] The inventors further developed the signaling mediated via the cytoplasmic tail of RAGE. Selective targeting of RAGE ligand-dependent signaling Regulation of transtransduction and / or RAGE ligand-independent transactivation is achieved using conventional techniques (Man Ligand-dependent RAGE suggested by igrasso, MB, et al 2016) Diaphanous-1 (Diaph1) may be an activation modulator. We showed that this can be achieved without adjusting the interaction with RAGE. , N-terminal truncated constructs of RAGE (e.g., RAGE 362-404 ) Adjuster The ability is maintained in the absence of Diaph1, thereby as described by the inventors. It has been confirmed that the modulating effect of the RAGE construct is independent of Diaph1.

[0040] Sakaguchi and his collaborators found that cells respond to RAGE ligand, S100A11, S When treated with 100A12, HMGB1, or AGE, the common pro-inflammatory adapter The proteins TIRAP, MyD88, and IRAK are overexpressed mainly in HEK293 cells. We found that it co-precipitates with RAGE and induces RAGE ligand-dependent activation of RAGE. TIRAP, MyD88, and IRAK eliminate TLR-3, which activates NFκB transcription. Because it also functions as an adapter protein for all Toll-like receptors (TLRs), These interactions are not specific to RAGE.

[0041] Following this research, the group developed S391E-RAGE 387-395 (RAGE(E )-I) mimics the phosphorylation state of RAGE and sequestrates the adapter protein TIRAP. By preventing endogenous RAGE signaling, RAGE lignan Specific aspects of signal-dependent signaling (i.e., inhibition of apoptosis, cell migration, and invasion) A study proposing it as an inhibitor was published (Putranto et al., 2013). However, the inventors have shown that phosphorylation is not necessary for RAGE activation. Furthermore, sequestering these common adapter proteins is possible with TLRs (e.g., T It also affects signal transduction via LR-2 and TLR-4, and some of these are related to RAG It can also be activated by E ligands (e.g., the s100 protein), and this This seems to explain Puranto et al.'s findings. In the same experiment, Puranto et al. S391A-RAGE 387-395 However, it did not show a recognizable connection to TIRAP. Because it did not attenuate apoptosis induced by RAGE ligand S100B. They also argued that it was not an appropriate inhibitor (Putranto et al., 2013). Puranto et al. evaluated it by determining the intracellular adenosine triphosphate content. Thus, since the growth of U-87MG cells was not significantly affected, S391E-RAG E 387-395 However, it did not inhibit all RAGE ligand-induced signaling pathways. We also paid attention to this (Putranto et al., 2013). Therefore, Putr The RAGE ligand-dependent pathway and P were presumably inhibited by anto and his collaborators. The cytoplasmic tail fragment of RAGE used by uranto et al. is the subject of this invention, RAGE ligand-independent activation by existing activated GPCRs and modulators This is clearly different. In fact, S391A-RAGE 387-395 Puranto The negative findings of Putranto et al. teach us to move away from the present invention. al, in all respects of this publication, discusses the cytoplasmic side of RAGE mediated by coexisting GPCRs. This does not aim for RAGE ligand-independent activation of the tail.

[0042] European Patent Application Publication No. 1415997-A1 describes the direct connection of the cytoplasmic tail of RAGE. It binds indirectly or indirectly, thereby producing signals from the binding of the ligand to RAGE. Inhibits or enhances signal transduction and subsequent NFκB activation, as well as the downstream pathways resulting from that activation. The identification and use of polypeptides are described in detail. This invention differs in many respects from this teaching. Firstly, this instruction concerns RAGE-mediated RAGE ligand-independent signaling or RAGE-mediated RAGE ligand-dependent signaling and RAGE ligand-independent signaling This is not intended to create a dual inhibition with Nal transmission. Secondly, European Patent Application Publication No. 14159 The claims of specification 97A1 relate to the unidentified element of the cytoplasmic tail of RAGE. This relates to the use of polypeptides for this purpose. In contrast, the inventors of RAGE on the cytoplasmic side The polypeptide encoding the tail and its variants are RAGE ligands via RAGE. Independent signaling or RAGE ligand-dependent signaling via RAGE and R Selectively binds signaling molecules associated with AGE ligand-independent signaling. It can be used for subsequent NFκB activation and downstream pathways arising from that activation. We demonstrated that this leads to regulation. Thirdly, we demonstrated that the weight of the cytoplasmic tail of RAGE Using selectively modified polypeptides containing essential elements, RA is transmitted via RAGE. We demonstrated the ability to regulate GE ligand-independent signaling. Fourthly, via RAGE The modulation of RAGE ligand-dependent signaling is described in European Patent Application Publication No. 1415997- Not shown in specification A1. Furthermore, specified in European Patent No. 1415997-A1. The only polypeptide capable of modulating RAGE ligand-dependent signaling in a physiologically identified manner. PK is a well-known binding partner and signaling mediator of full-length RAGE. It is Cζ. The inventors have shown that PKCζ is not necessary for the operation of those modulators. This indicates that.

[0043] After binding to CpG-DNA, RAGE uses an F-box protein at cytosolic residue K374. Monoubiquitination by FBXO10, followed by endocytosis and lysosomes. It causes mediated degradation (Evankovich et al. 2017). Endosight Ubiquitination of RAGE and / or cis is observed with other pro-inflammatory RAGE ligands. It hasn't been done.

[0044] RAGE ubiquitination is partially dependent on S391, and S391A-RAGE The mutant is partially tolerant to ubiquitination and subsequent degradation after FBXO10 overexpression. It has a sex.

[0045] These data suggest that K374R and S391A-RAGE variants are ubiquitous under certain circumstances. It may be resistant to chitinization, which allows it to accumulate at a higher level than wild-type RAGE. This suggests that... However, this potentially increased stability / resistance to degradation is... As detailed below, RAGE activation of coexisting GPCRs is RAGE ligand-independent. S391 is still present even in the presence of rapid sexualization regulation and 1000 times more wild-type RAGE being delivered. RAGE ligand-independent RAGE signaling achieved by A-RAGE mutants The inhibition of sexual activation could not be explained, and this regulation occurred in the presence and absence of K374. They don't occur in the same way.

[0046] The present inventors have stated that, although this does not limit the universality of the following description of the present invention, Ang II The activity of specific coexisting GPCRs, such as AT1R or CCR2, induced by MCP-1, etc. We demonstrated that this process triggers activation of the coexisting cytoplasmic tail of RAGE. This activation is This occurs in the absence of the extracellular domain of RAGE, and therefore the RAGE ligand or RA Their interactions with the extracellular domain of GE are completely independent. (Theory constraints) Although we do not wish this to happen, the inventors have found that certain coexisting GPCRs can trigger RAGE. We believe that Lance activation represents the main mechanism of RAGE activation. In line with this premise... The inventors of this invention have found that RAGE-ligand-dependent signaling remains completely absent. Furthermore, RAGE ligand-independent in AGER / apoE double knockout (DKO) mice. Selective restoration of RAGE signaling was observed in RAGE-rich apoE-KO mice. We demonstrated that atheroma formation could be restored to a level not significantly different from that of the previously treated area.

[0047] Many of the harmful signaling events induced by AT1R activation are related to RAGE expression. If it is absent (for example, gene deletion or silencing, or RAGE is generated) In healthy cells that do not exhibit this behavior, or in ligand-independent activation of RAGE by activated AT1R, It attenuates (when it is prevented or inhibited).

[0048] At the same time, inositol phosphate and calcium, which are inhibited by AT1R antagonists, Gq signaling pathways, etc., which are induced by AT1R activation that leads to the induction of saturation. The RAGE-independent AT1R signaling pathway is affected by RAGE deletion and RAGE expression. It is unaffected by inhibition of single or RAGE function.

[0049] Therefore, RAG by specific activated coexisting GPCRs such as AT1R or CCR2 E-ligand-independent modulation, particularly inhibition, of RAGE activation follows activation of coexisting GPCRs. This offers specific advantages to therapeutic interventions targeting pathogenic signaling induced via AGEs. For example, such a modulator, in certain embodiments, impairs blood pressure regulation. Without any effect, or after AT1R inhibition which limits the use of RAAS inhibitors, etc. Without inducing feedback "avoidance" from AT1R inhibition, the adverse effects of AT1R This enables proactive targeting. Such modulators allow this transactivation pathway to Constitutively activated (e.g., leukocytes, endothelial cells) or induced (e.g., inflammation and It can only affect cells and tissues (at the site of injury), and RAGE does not express cells (for example, healthy cells). RAAS and other GPCR-mediated signaling in smooth muscle cells remain unaffected. do.

[0050] Activation of AT1R has both hemodynamic and non-hemodynamic effects. Hemodynamic effect This refers to changes in blood flow, including blood volume, blood pressure, flow rate or velocity, resistance, and cardiac output. This includes changes in turbulence and wall tension. AT1R blockers (inhibitors) affect hemodynamics (for example) (For example, it lowers blood pressure, alters resistance and cardiac output) and has non-hemodynamic effects (e.g., oxidation It can exhibit both (causing both stress and inflammation). RAAS is activated ( For example, in heart disease, kidney disease, and hypertension, both hemodynamic and non-hemodynamic pathways are activated. It will be done.

[0051] RAGE ligand-independent RAGE activation by activated AT1R is due to AT1R activation. It is a mediator of only non-hemodynamic (non-blood flow) effects. The inventors of RAGE Somatic gene deletions do not have direct hemodynamic effects (e.g., blood pressure, vascular resistance, or blood flow). (Does not affect blood volume), and does not alter the hemodynamic effects of AT1R activation or inhibition. We observed the following: Targeting RAGE ligand-independent RAGE activation by activated AT1R. The main advantage of this is that the procedure becomes unsafe due to harmful hemodynamic effects. This means not being limited by the constraints of blood pressure regulation that previously restrict how much blood pressure can be lowered.

[0052] Furthermore, changes in blood flow automatically trigger a feedback (homeostatic) response, which alters blood flow. Maintain at a constant level. These feedback responses are AT1R inhibition or angiotenosis. To counteract or avoid the hemodynamic effects of RAAS inhibition by inhibiting syn-converting enzyme (ACE). It acts in such a way. In contrast, RAG mediated by activated angiotensin receptors such as AT1R RAAS activation is achieved through E-ligand-independent inhibition of RAGE activation. The selective inhibition of the resulting non-hemodynamic pathways is not related to feedback / avoidance responses. The lack of such feedback response underscores the durability and effectiveness of such inhibition.

[0053] <Modules of RAGE ligand-independent RAGE activation by activated coexisting GPCRs> Writer> In one embodiment, the present invention includes a modulator of RAGE activity, and such RAGE E activity is induced by specific coexisting active GPCRs.

[0054] In one embodiment, the present invention relates to a RAGE ligand mediated by a specific activated coexisting GPCR. Includes a modulator for RAGE activation that is independent of RAGE activation.

[0055] In one embodiment, the present invention relates to RA induced by specific activated coexisting GPCRs. It includes modulators that are modulators of GE-dependent signaling.

[0056] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of sexual RAGE activation acts in the absence of the RAGE ligand.

[0057] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of RAGE activation in the presence of a severed external domain of RAGE It acts.

[0058] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulators of sexual RAGE activation are those with a length of 40 amino acids or less, and 20 amino acids or less. The presence of a cleaved external domain of RAGE consisting of 10 amino acids or less, or 5 amino acids or less. It operates below.

[0059] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. Sexual RAGE activation modulators are those with a length greater than 5 amino acids, greater than 10 amino acids, or 20 amino acids. Conjugates the amino acid-rich transmembrane domain analog, fragment, or derivative of RAGE. It contains the entire extracellular domain of RAGE.

[0060] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of RAGE activation is the RAGE ligand-binding external domain of RAGE. It operates in the absence of [something].

[0061] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The sex-activated RAGE modulator does not contain the extracellular domain of RAGE.

[0062] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. Sexual RAGE activation modulators are analogs, fragments, or of the extracellular domain of RAGE. It does not contain derivatives.

[0063] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The RAGE activation modulator contains a fragment of the extracellular domain of RAGE.

[0064] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulators of sexual RAGE activation are those with a length of 40 amino acids or less, and 20 amino acids or less. Contains fragments of the extracellular domain of RAGE, which have 10 amino acids or fewer, or 5 amino acids or fewer. .

[0065] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The sex-mediated modulator of RAGE activation does not bind to the extracellular domain of RAGE.

[0066] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of sexual RAGE activation is induced by activated coexisting GPCRs. It inhibits or promotes signal transduction that occurs via the C-terminal cytoplasmic tail of RAGE.

[0067] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of RAGE activation is the bubbling that occurs in the C-terminal cytoplasmic tail of RAGE. It inhibits the synthesis.

[0068] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of RAGE activation in sexuality involves the transmembrane domain of RAGE and specific GPCRs. It inhibits or promotes the interaction between them.

[0069] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. Modulators of RAGE activation of the nature inhibit the interaction between the transmembrane domain of RAGE and a specific GPCR and that of a specific GPCR.

[0070] In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. or promote.

[0071] In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR. do.

[0072] In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. or promote, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. side tail.

[0073] In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit or promote the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR, and inhibit or promote the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. In one embodiment of the present invention, modulators of RAGE ligand-independent RAGE activation by a specific activated co-existing GPCR inhibit the ability of an activated GPCR to regulate RAGE-dependent signal transduction that depends on the proximity between the transmembrane domain of RAGE and the specific GPCR. and inhibit the signal transduction that occurs through the C-terminal cytoplasmic tail of RAGE induced by the activated co-existing GPCR. Inhibit the signal transduction occurring through

[0074] Throughout this specification, unless the context requires otherwise, coexisting GPCRs are G protein-coupled receptors that are co-expressed in the same cells as RAGE, either endogenously or as a result of transfection, and are members of the G protein-coupled receptor superfamily (GPCRs; seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and also known as G protein-linked receptors; some other 7TM proteins include GPR107, GPR137, OR51E 1, TPRA1, GPR143, and GPR157, and are classified as members of the G protein-coupled receptor superfamily). Not all members of this superfamily are coupled to G proteins, and in this regard, it should be noted that the term GPCR includes members of the superfamily that are not coupled to G proteins. Co-expression in the same cell can be demonstrated by many techniques known to those skilled in the art, including co-immunoprecipitation, bioluminescence resonance energy transfer (B RET), fluorescence resonance energy transfer (FRET), and microscopy. Coexisting GPCRs are preferably GPCRs that are sufficiently close to RAGE such that a functional interaction occurs between the GPCR and RAGE. Even more preferably, coexisting GPCRs are GPCRs that are sufficiently close to RAGE such that an appropriate proximity assay can detect this proximity. Examples of appropriate proximity assays are BRET, F RET, enzyme fragment complementation, split luciferase complementation, split fluorophore complementation, TANGO assay, NanoLuc Binary Technology (Nan oBIT) assay, proximity ligation assay (PLA), or these proteins is a GPCR that is sufficiently close to RAGE such that a functional interaction occurs between the GPCR and RAGE. Even more preferably, coexisting GPCRs are GPCRs that are sufficiently close to RAGE such that an appropriate proximity assay can detect this proximity. Examples of appropriate proximity assays are BRET, F RET, enzyme fragment complementation, split luciferase complementation, split fluorophore complementation, TANGO assay, NanoLuc Binary Technology (Nan oBIT) assay, proximity ligation assay (PLA), or these proteins Whether one or more of them are labeled or tagged to facilitate the use of the assay. Regardless, any other proximity assay capable of detecting the proximity of two proteins. Such proximity assays can be constructed in different ways, using receptor-heteromer investigation techniques (R The configuration of eceptor-HIT and its derivatives are preferred for such proximity assays. This is the structure (International Publication No. 2008 / 055313 pamphlet; Jaeger et al. al., 2014).

[0075] Throughout this specification, unless the context requires otherwise, activated GPCRs This is a combination of an agonist, a subagonist and / or an allosteric modulator. This can result from and / or from constitutive activity that does not require ligand binding, leading to an active state. This refers to a specific GPCR.

[0076] Throughout this specification, unless the context requires otherwise, the specific activation of the present invention will not be used. The coexisting GPCRs are expressed in the same cells as RAGE, and regulate RAGE activation and / or The influence on RAGE, which indicates the modulation of RAGE-dependent signaling induction, is specific to coexisting GPs. Detected when CR is activated by a recognition ligand or when GPCRs are constitutively active. It is a GPCR.

[0077] In one embodiment, the effect on RAGE, which shows regulation of RAGE activation, is recognized by coexisting GPCRs. Using bioluminescent resonance energy transfer (BRET) during ligand attachment, Lucifer - Fluorophores labeled with RAGE conjugates (RAGE / Rluc8, etc.) Rab1, Rab4, Rab5, Rab6, Rab7, Rab8, Rab9 and / or Rab11 and other Rab(Venus-Rab1, Venus-Rab4, Venus -Rab5, Venus-Rab6, Venus-Rab7, Venus-Rab8, V Intracellular compartments such as enus-Rab9 and / or Venus-Rab11 Fluorophore markers and / or K-ras (Venus-K-ras, etc.) These include those detected by changes in the proximity of plasma membrane markers such as djugate fragments. This is a change in intracellular transport (Tiulpakov et al., 2016).

[0078] In another embodiment, the effect on RAGE is that of luciferase-conjugated RAGE (RAGE-Rluc8, etc.), IQGAP-1, protein kinase C zeta (PK) Cζ), Dock7, MyD88, TIRAP, ERK1 / 2 (Jules et al. .,2013; Ramasamy et al.,2016), olfactory receptor 2T2, AD P / ATP translocase 2, protein phosphatase 1G, intercellular adhesion molecule 1, Protein DJ-1 (PARK7), Carponin-3, Drebrin, Filamin B, Ras Related proteins: Rab-13, radixin / ezrin / moesin, proteolipidotan Protein 2, Coronin, S100 A11, Succinyl-CoA ligase [GDP formation] Buunit α, Hsc70 interacting protein, apoptosis inhibitor 5, neuropilin , cleavage stimulant, growth factor receptor-binding protein 2, sec61β subunit or Nc k1 and other fluorophore-labeled proteins that interact with the cytoplasmic tail of RAGE. RAGE-dependent interactions, such as those detected by changes in proximity to the RAGE interaction group, This is a change in the Gunar transmission.

[0079] In another embodiment, the effect on RAGE is measured by one or more of the following Changes in the standard activation of NFκB upon activation of specific co-existing GPCRs by recognition ligands such as those detected by changes in RAGE-dependent signaling. · Monitoring the phosphorylation of substrates such as GST-IκBα in vitro to determine the activity of IkB kinase (IKK); · Detection of IkB degradation kinetics, including phosphorylation / ubiquitination and / or degradation of IκB and / or IκB-α; · Detection of phosphorylation / ubiquitination of p65 (Rel-A) by, for example, the use of antibodies, gel shift, EMSA, and / or mass spectrometry; · Detection of the cytosolic-to-nuclear transport / transfer of NFκB components / subunits such as p65 / phospho-p65; · Detection of dimerization / complex formation of NFκB subunits; · Detection of active NFκB components / subunits by binding to immobilized DNA sequences / oligonucleotides containing NFκB response elements / consensus NFκB binding motifs, for example, by use of electrophoretic mobility shift assay or gel shift assay, SELEX, protein binding microarray, or sequence-based approaches; · Chromatin immunoprecipitation (ChIP) assay to detect in situ binding of NFκB to the promoters and enhancers of specific genes; · In vitro kinase assay for NFκB kinase activity; · NFκB reporter assays via transgene expression of reporter constructs such as LacZ Fluc, eGFP SEAP, and NF-gluc using approaches such as plasmid transfection, reporter cell lines, minicircles, retroviruses, or lentiviruses; ​ Measurement of NFκB transcriptional activity using the Sei method; • Cytokines, growth factors, adhesion molecules, and mitochondrial anti-migration by real-time PCR Expression of downstream targets of NFκB, such as apoptotic genes, proteins, or functional assays. Measurement of changes (The multifaceted nature of NFκB is currently reflected in approximately 500 transcriptional targets) Please note the following (as of August 2, 2017, http: / / www.bu.edu / See nf-kb / gene-resources / target-genes / i)); and • Polkadots activity in T cells, adhesion in endothelial cells, activation in leukocytes, or tumorigenesis. Measurement of functional or structural changes induced by NFκB-dependent signaling, etc.

[0080] In another embodiment, the effect on RAGE is measured by N by measuring one or more of the following: RAGE signaling, such as that detected by changes in non-standard FκB activation. It is a change. • Detection of NIK (NFκB-induced kinase); • Detection of IKKα activation / phosphorylation; • Ability to autophosphorylate or phosphorylate substrates by performing kinase assays. Detection of NIK kinase activity by [method / tool]; • Generation of p52-containing NFκB dimers such as p52 / RelB; Detection of phospho-NFκB2p100 (Ser866 / 870); • Detection of the partial decomposition (called treatment) of precursor p100 to p52; • Detection of p52 / RelB transfer to the nucleus; • Detection of p52 / RelB binding to the NFκB site; Plasmid transduction, reporter cell lines, minicircles, retroviruses, or lentiform cell lines. Approaches using viruses, such as LacZ Fluc, eGFP SEAP, and NF NFκB reporter assay via transgene expression of reporter constructs such as -gluc Measurement of NFκB transcriptional activity using (i); and • Functional assays such as real-time PCR, protein expression, or CXCL12 Measurement of changes in the expression of downstream targets of non-standard NFκB signaling.

[0081] <Coexisting GPCR> In one embodiment, a specific activated coexisting GPCR of the present invention is used in the same cells as RAGE. It is a GPCR that is expressed and associated with RAGE-related disorders.

[0082] In one embodiment, a specific activated coexisting GPCR of the present invention is used in the same cells as RAGE. These are expressed, associated with RAGE-related disorders, and their removal and / or inhibition can lead to R This GPCR is known to reduce or alleviate AGE-related disorders.

[0083] In one embodiment, the specific activated coexisting GPCR of the present invention is associated with inflammation. It is a GPCR.

[0084] In one embodiment, a specific activated coexisting GPCR of the present invention is associated with inflammation. Furthermore, these GPCRs, whose removal and / or inhibition result in a reduction or alleviation of inflammation, ru.

[0085] In one embodiment, a specific activated coexisting GPCR of the present invention is related to cell proliferation. It is a GPCR.

[0086] In one embodiment, a specific activated coexisting GPCR of the present invention is related to cell proliferation. Furthermore, the removal and / or inhibition of these GPs results in a reduction or mitigation of cell proliferation. It's CR.

[0087] In fact, there is evidence that many GPCRs are involved in inflammation to some extent, and these levels are... They can be distinguished according to the level of evidence. 1 - No evidence has been found to date; 2 - The receptor structure or motif within the receptor is a known inflammatory / immune receptor or inflammatory / immune receptor. It is similar to motifs involved in the epidemic process; 3 - Receptors bind to ligands that mediate inflammatory / immune processes; 4 - Receptors are associated with / involved in inflammatory / immune diseases; 5 - At least one has described the direct involvement of receptors in inflammatory / immune processes. Another paper; 6 - Receptors are expressed in inflammatory / immune cells; and 7 - The involvement of receptors in inflammatory / immune processes is well characterized (ht The database at http: / / www.guidetopharmacology.org is listed. (As stated).

[0088] Current understanding of Family A GPCRs (excluding olfactory, vomeronasal, and opsin) and their involvement in inflammation Evidence level (see the key above):

[0089] [Table 1]

[0090] [Table 2]

[0091] [Table 3]

[0092] [Table 4]

[0093] [Table 5]

[0094] [Table 6]

[0095] [Table 7]

[0096] [Table 8]

[0097] Family A olfactory GPCRs and the current level of evidence regarding their involvement in inflammation (see the key above). (I want to be)

[0098] [Table 9]

[0099] [Table 10]

[0100] [Table 11]

[0101] [Table 12]

[0102] [Table 13]

[0103] [Table 14]

[0104] [Table 15]

[0105] [Table 16]

[0106] [Table 17]

[0107] Family A vomeronasal and opsin GPCRs and the current level of evidence regarding their involvement in inflammation (see above) Please refer to the key):

[0108] [Table 18]

[0109] Family B GPCRs and the current level of evidence regarding their involvement in inflammation (see the keys above) sea ​​bream):

[0110] [Table 19]

[0111] [Table 20]

[0112] Family C GPCRs and the current level of evidence regarding their involvement in inflammation (see the keys above) sea ​​bream):

[0113] [Table 21]

[0114] Frizzled family GPCRs and the current level of evidence regarding their involvement in inflammation (see above) Please refer to the following):

[0115] [Table 22]

[0116] Along with other 7TM proteins classified as members of the GPCR superfamily, Current level of evidence regarding its involvement in inflammation (see the key above):

[0117] [Table 23]

[0118] In one embodiment, the specific activated coexisting GPCR of the present invention is group ADGRA2, ADGRB2, ADGRB3, ADGRF3, ADGRG4, ADGRV1, CELSR 1. CELSR2, CELSR3, OX1 receptor, OX2 receptor, PTH1 receptor, PT H2 receptor, AMY1 receptor, AMY2 receptor, AMY3 receptor, AM1 receptor, AM2 Receptors, GPR63, GPR75, NMU2 receptor, OPN5, V1B receptor, y6 receptor Body, 5-HT4 receptor, GPR101, GPR119, GPR135, GPR137, G PR141, GPR149, GPR150, GPR151, GPR152, GPR157 , GPR19, GPR25, GPR37, GPR37L1, GPR50, GPR62, L GR5, MRGPRE, MRGPRF, NTS2 receptor, OPN4, OPN4, OR10 A7, OR10AG1, OR10Q1, OR10W1, OR12D3, OR13C2, O R13C3, OR13C4, OR13C5, OR13C8, OR13F1, OR13G1 , OR1A2, OR1L1, OR1S1, OR1S2, OR2AK2, OR2D2, OR 2D3, OR4A15, OR4C11, OR4C12, OR4C13, OR4C15, O R4C16, OR4K13, OR4K14, OR4K15, OR4K17, OR4N5, OR5AC2, OR5AK2, OR5AP2, OR5AR1, OR5AS1, OR5B1 2, OR5B17, OR5B2, OR5B21, OR5B3, OR5D13, OR5D1 4, OR5D16, OR5D18, OR5F1, OR5I1, OR5J2, OR5K3, OR5L1, OR5L2, OR5M1, OR5M10, OR5M11, OR5M3, OR 5M8, OR5M9, OR5R1, OR5T1, OR5T2, OR5T3, OR5W2, OR6C74, OR6K6, OR6M1, OR6Q1, OR6X1, OR8H1, OR8 H2, OR8H3, OR8J1, OR8J3, OR8K1, OR8K3, OR8K5, O R8U1, OR8U8, OR9A4, OR9G1, OR9G4, OR9G9, OR9Q2 TAAR3, TPRA1, Y4 receptor, 5-HT1D receptor, 5-HT1E receptor, A DGRB1, AT2 receptor, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor Condition, CRF2 receptor, ETA receptor, ETB receptor, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1, GABAB2, GAL1 receptor GIP receptor, GLP-1 receptor, GLP-2 receptor, glucagon receptor, GnRH2 Receptors, GPER, GPR107, GPR139, GPR156, GPR158, GPR 161, GPR171, GPR179, GPR39, GPR45, GPR88, GPRC 5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, L PA3 receptor, LPA4 receptor, MC2 receptor, MC4 receptor, mGlu2 receptor, mG lu3 receptor, motilin receptor, MRGPRD, MRGPRX1, MRGPRX3, NK 2 receptors, NPFF1 receptor, NPFF2 receptor, NPS receptor, NTS1 receptor, OR 1D2, OR2AG1, OT receptor, PAC1 receptor, RXFP1 receptor, secretin receptor Body temperature, TSH receptor, UT receptor, V1A receptor, V2 receptor, α2A-adrenergic receptor Condition, α2B-adrenergic receptor, α2C-adrenergic receptor, β1-adrenergic Receptors, β3-adrenergic receptor, 5-HT1B receptor, 5-HT1F receptor, 5-H T2B receptor, 5-HT2C receptor, 5-HT5A receptor, 5-HT6 receptor, 5-HT 7 receptors, ADGRE4P, ADGRF1, ADGRG1, ADGRG3, ADGRG5 Calcitonin receptor-like receptor, CB1 receptor, CB2 receptor, CCK1 receptor, CCK D2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor FFA1 receptor, FFA3 receptor, FSH receptor, FZD1, FZD2, FZD3, G HRH receptor, GnRH1 receptor, GPBA receptor, GPR1, GPR119, GPR1 2, GPR142, GPR143, GPR146, GPR148, GPR153, GPR 160, GPR162, GPR17, GPR173, GPR174, GPR176, GP R18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61, GPR78, GPR82, GPR83 GPR84, GPR85, GPR87, GPRC5D, GPRC6 receptors, HCA2 receptors Condition, HCA3 receptor, kispeptin receptor, LGR4, LGR6, LH receptor, LPA 2 receptors, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor Condition, MAS1L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor NPBW2 receptor, OPN3, OR11H1, OR2A1, OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, OR2C1, OR2C3, OR 2J3, OR2L13, OR2T11, OR2T34, OR2W3, OR3A3, OR4 D10, OR4M1, OR4Q3, OR51A2, OR51A4, OR51A7, OR5 1B2, OR51B4, OR51B5, OR51B6, OR51D1, OR51E1, O R51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2 , OR51I1, OR51I2, OR51J1, OR51L1, OR51M1, OR51 Q1, OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR 52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I 1, OR52I2, OR52J3, OR52K1, OR52K2, OR52L1, OR5 2M1, OR52N1, OR52N2, OR52N4, OR52N5, OR52R1, O R52W1, OR56A1, OR56A3, OR56A4, OR56A5, OR56B1 OR56B4, OR6V1, OR7D2, OR9A2, oxoglutarate receptor, P2 RY10, P2RY8, P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP Receptors, RXFP2 receptor, RXFP4 receptor, sst1 receptor, sst2 receptor, ss t3 receptor, sst4 receptor, sst5 receptor, TA1 receptor, TAAR2, TAAR5 , TAAR6, TAAR8, TAAR9, TAS1R1, TAS1R2, TAS1R3, TAS2R1, TAS2R10, TAS2R13, TAS2R14, TAS2R16, T AS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31, TA S2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41, TAS 2R42, TAS2R43, TAS2R45, TAS2R46, TAS2R5, TAS2 R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor Y1 receptor, Y2 receptor, Y5 receptor, α1A-adrenergic receptor, α1B-adrenergic receptor Narin receptor, α1D-adrenergic receptor, δ receptor, 5-HT1A receptor, 5-HT 2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, ACKR1, AC KR2, ACKR3, ACKR4, ADGRE1, ADGRE2, ADGRE3, ADG RE5, Apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP receptor) Body, BLT1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor Body, CaS receptor, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1 , CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, Cys LT1 receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP 2 receptors, EP3 receptors, EP4 receptors, FFA2 receptors, FFA4 receptors, FP receptors FPR1, FPR2 / ALX, FPR2 / ALX, FPR3, FZD6, GAL2 receptor Body, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR 183, GPR21, GPR31, GPR32, GPR34, GPR4, GPR55, G PR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor LPA5 receptor, MAS1, MC1 receptor, MCH1 receptor, mGlu1 receptor, mG lu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor Condition, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y11 receptor, P2Y13 Receptors, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1 PAR2, PAR3, PAR4, PKR1, PKR2, S1P1 receptor, S1P2 receptor Body, S1P3 receptor, S1P4 receptor, S1P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1, β2-adrenergic receptor, κ receptor It is a GPCR selected from the μ receptor.

[0119] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph

[0095] of the international publication of the application.

[0120] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph

[0095] of the international publication of the application.

[0121] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GPC selected from the group of paragraphs

[0095] in the International Publication of this Application, It is R.

[0122] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5, Except for CCR10 and CXCR3, paragraph

[0095] of the International Publication of this Application It is a GPCR selected from the group.

[0123] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR8, CCR10, CXCR1, CXCR3, CX CR6, CXCR7, dopamine D2 receptor, glucagon-like peptide receptor 1, neuro Tensin NTS2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, Prostaglandin E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor Except for the somatostatin 3 receptor, the international publication of this application in the international publication gazette of this application This is a GPCR selected from the group in paragraph

[0095] of the publication.

[0124] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR4, CCR5, CCR8, CCR10, CXCR 1. CXCR3, CXCR6, CXCR7, dopamine D2 receptor, glucagon-like peptide Prostaglandin receptor 1, neurotensin NTS2 receptor, platelet-activating factor receptor, prostaglandin Prostaglandin E2 receptor, prostaglandin E3 receptor, prostaglandin E4 receptor, Except for the matostatin 1 receptor and somatostatin 3 receptor, the international publication of this application is available. It is a GPCR selected from the group in paragraph

[0095] .

[0125] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, M2 receptor and OX1 receptor, the international publication of this application contains This is a GPCR selected from the group in paragraph

[0095] .

[0126] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR4, M2 receptor and OX1 receptor, the international publication of this application This is a GPCR selected from the group in paragraph

[0095] of the report.

[0127] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR5, M2 receptor and OX1 receptor, the international publication of this application This is a GPCR selected from the group in paragraph

[0095] of the report.

[0128] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, M2 receptor and OX1 receptor, the present application It is a GPCR selected from the group in paragraph

[0095] of the International Publication.

[0129] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Apelin receptor, CCR3, CCR8, CC R10, CXCR1, CXCR3, CXCR6, CXCR7, dopamine D2 receptor, Lucagon-like peptide receptor 1, M2 receptor, neurotensin NTS2 receptor, OX1 receptor Condition, platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin E 3 receptors, prostaglandin E4 receptor, somatostatin 1 receptor and somatostatin With the exception of 3 receptors, selected from the group in paragraph

[0095] of the International Publication of this Application It is a GPCR.

[0130] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Condition, CCR3, CCR4, CCR5, CCR10, CXCR3, M2 receptor, OX1 receptor Apart from the contents, G selected from the group of paragraphs

[0095] in the International Publication of this Application. It's PCR.

[0131] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Aperin receptor, CCR3, CCR4, CC R5, CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Do Pamine D2 receptor, glucagon-like peptide receptor 1, M2 receptor, neurotensin NT S2 receptor, OX1 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, Prostaglandin E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor Except for the body and somatostatin 3 receptor, paragraph

[0009] of the International Publication of this Application It is a GPCR selected from group [5].

[0132] In one embodiment, the specific activated coexisting GPCR of the present invention is the group OX1 receptor, OX2 receptor, PTH1 receptor, PTH2 receptor, AMY1 receptor, AMY2 receptor, A MY3 receptor, AM1 receptor, AM2 receptor, GPR63, GPR75, NMU2 receptor OPN5, V1B receptor, y6 receptor, 5-HT4 receptor, GPR101, GPR11 9, GPR135, GPR137, GPR141, GPR149, GPR150, GPR 151, GPR152, GPR157, GPR19, GPR25, GPR37, GPR3 7L1, GPR50, GPR62, LGR5, MRGPRE, MRGPRF, NTS2 reception Condition, OPN4, OPN4, OR10A7, OR10AG1, OR10Q1, OR10W 1, OR12D3, OR13C2, OR13C3, OR13C4, OR13C5, OR1 3C8, OR13F1, OR13G1, OR1A2, OR1L1, OR1S1, OR1S 2, OR2AK2, OR2D2, OR2D3, OR4A15, OR4C11, OR4C1 2, OR4C13, OR4C15, OR4C16, OR4K13, OR4K14, OR4 K15, OR4K17, OR4N5, OR5AC2, OR5AK2, OR5AP2, OR 5AR1, OR5AS1, OR5B12, OR5B17, OR5B2, OR5B21, O R5B3, OR5D13, OR5D14, OR5D16, OR5D18, OR5F1, O R5I1, OR5J2, OR5K3, OR5L1, OR5L2, OR5M1, OR5M1 0, OR5M11, OR5M3, OR5M8, OR5M9, OR5R1, OR5T1, O R5T2, OR5T3, OR5W2, OR6C74, OR6K6, OR6M1, OR6Q 1, OR6X1, OR8H1, OR8H2, OR8H3, OR8J1, OR8J3, OR 8K1, OR8K3, OR8K5, OR8U1, OR8U8, OR9A4, OR9G1, OR9G4, OR9G9, OR9Q2, TAAR3, TPRA1, Y4 receptor, 5HT 1D receptor, 5-HT1E receptor, ADGRB1, AT2 receptor, BB1 receptor, BB3 Receptors, CGRP receptor, CRF1 receptor, CRF2 receptor, ETA receptor, ETB receptor Body, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABA B1, GABAB2, GAL1 receptor, GIP receptor, GLP-1 receptor, GLP-2 receptor Condition, glucagon receptor, GnRH2 receptor, GPER, GPR107, GPR139, GPR156, GPR158, GPR161, GPR171, GPR179, GPR39 GPR45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, LPA3 receptor, LPA4 receptor, MC2 receptor, M C4 receptor, mGlu2 receptor, mGlu3 receptor, motilin receptor, MRGPRD, M RGPRX1, MRGPRX3, NK2 receptor, NPFF1 receptor, NPFF2 receptor, NPS receptor, NTS1 receptor, OR1D2, OR2AG1, OT receptor, PAC1 receptor Body, RXFP1 receptor, secretin receptor, TSH receptor, UT receptor, V1A receptor, V2 receptor, α2A-adrenergic receptor, α2B-adrenergic receptor, α2C-adrenergic receptor Renaline receptor, β1-adrenergic receptor, β3-adrenergic receptor, 5-HT1B Receptors, 5-HT1F receptor, 5-HT2B receptor, 5-HT2C receptor, 5-HT5A Receptors, 5-HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1, ADG RG1, ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, C B2 receptor, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSH receptor FZD1, FZD2, FZD3, GHRH receptor, GnRH1 receptor, GPBA receptor , GPR1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR148, GPR153, GPR160, GPR162, GPR17, GPR173 , GPR174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61, GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC 5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor, cyspeptin receptor, LG R4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor Body, M3 receptor, M4 receptor, M5 receptor, MAS1L, MC3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPR G, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, O R2A1, OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2 B6, OR2C1, OR2C3, OR2J3, OR2L13, OR2T11, OR2T3 4, OR2W3, OR3A3, OR4D10, OR4M1, OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51B4, OR51B5, OR51B 6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR5 1F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, O R51L1, OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1 , OR52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52 B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR 52E8, OR52H1, OR52I1, OR52I2, OR52J3, OR52K1, OR52K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N 4, OR52N5, OR52R1, OR52W1, OR56A1, OR56A3, OR5 6A4, OR56A5, OR56B1, OR56B4, OR6V1, OR7D2, OR9 A2, oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y 4 receptors, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, s st1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, T A1 receptor, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1 R1, TAS1R2, TAS1R3, TAS2R1, TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, T AS2R30, TAS2R31, TAS2R38, TAS2R39, TAS2R4, TA S2R40, TAS2R41, TAS2R42, TAS2R43, TAS2R45, TA S2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2 R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, α1A- Adrenergic receptors, α1B-adrenergic receptors, α1D-adrenergic receptors, δ receptors Receptor, 5-HT1A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor Condition, A3 receptor, ACKR1, ACKR2, ACKR3, ACKR4, ADGRE1, ADGRE2, ADGRE3, ADGRE5, Apelin receptor, AT1 receptor, B1 receptor Body, B2 receptor, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor Condition, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1, CCR10, CCR 2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR L2, chemerin receptor, CX3CR1, CXCR1, CXCR2, CXCR3, CXCR 4. CXCR5, CXCR6, CysLT1 receptor, CysLT2 receptor, DP1 receptor DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 Receptors, FFA4 receptor, FP receptor, FPR1, FPR2 / ALX, FPR2 / ALX FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR13 2, GPR15, GPR18, GPR183, GPR21, GPR31, GPR32, G PR34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, MAS1, MC1 receptor, MC H1 receptor, mGlu1 receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, M T2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor Condition, P2Y11 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2 Y6 receptor, PAF receptor, PAR1, PAR2, PAR3, PAR4, PKR1, PK R2, S1P1 receptor, S1P2 receptor, S1P3 receptor, S1P4 receptor, S1P5 receptor Condition, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1, It is a GPCR selected from β2-adrenergic receptors, κ receptors, and μ receptors.

[0133] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000109] of the international publication of the application.

[0134] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000109] of the international publication of the application.

[0135] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000109] in the International Publication of this Application, It's CR.

[0136] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5, Except for CCR10 and CXCR3, paragraph [000109 It is a GPCR selected from the group ].

[0137] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR8, CCR10, CXCR1, CXCR3, CX CR6, CXCR7, dopamine D2 receptor, glucagon-like peptide receptor 1, neuro Tensin NTS2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, Prostaglandin E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor Except for the somatostatin 3 receptor, paragraph

[00010] of the International Publication of this Application It is a GPCR selected from group [9].

[0138] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR4, CCR5, CCR8, CCR10, CXCR 1. CXCR3, CXCR6, CXCR7, dopamine D2 receptor, glucagon-like peptide Prostaglandin receptor 1, neurotensin NTS2 receptor, platelet-activating factor receptor, prostaglandin Prostaglandin E2 receptor, prostaglandin E3 receptor, prostaglandin E4 receptor, Except for the matostatin 1 receptor and somatostatin 3 receptor, the international publication of this application is available. It is a GPCR selected from the group in paragraph [000109].

[0139] In one embodiment, the specific activated coexisting GPCRs of the present invention are group: OX1 receptor, O X2 receptor, PTH1 receptor, PTH2 receptor, AMY1 receptor, AMY2 receptor, AM This GPCR is selected from among the Y3 receptor, AM1 receptor, and AM2 receptor.

[0140] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, M2 receptor and OX1 receptor, the international publication of this application contains This is a GPCR selected from the group in paragraph [000109].

[0141] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR4, M2 receptor and OX1 receptor, the international publication of this application This is a GPCR selected from the group in paragraph [000109] of the report.

[0142] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR5, M2 receptor and OX1 receptor, the international publication of this application This is a GPCR selected from the group in paragraph [000109] of the report.

[0143] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, M2 receptor and OX1 receptor, the present application It is a GPCR selected from the group in paragraph [000109] of the International Publication.

[0144] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Apelin receptor, CCR3, CCR8, CC R10, CXCR1, CXCR3, CXCR6, CXCR7, dopamine D2 receptor, Lucagon-like peptide receptor 1, M2 receptor, neurotensin NTS2 receptor, OX1 receptor Condition, platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin E 3 receptors, prostaglandin E4 receptor, somatostatin 1 receptor and somatostatin With the exception of 3 receptors, selected from the group in paragraph [000109] of the International Publication of this Application It is a GPCR.

[0145] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Condition, CCR3, CCR4, CCR5, CCR10, CXCR3, M2 receptor and OX1 Excluding the receptor, selected from the group of paragraphs [000109] in the International Publication of this Application It is a GPCR.

[0146] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Aperin receptor, CCR3, CCR4, CC R5, CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Do Pamine D2 receptor, glucagon-like peptide receptor 1, M2 receptor, neurotensin NT S2 receptor, OX1 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, Prostaglandin E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor Except for the body and somatostatin 3 receptor, paragraph

[0001] of the International Publication of this Application This is a GPCR selected from group

[09] .

[0147] In one embodiment, the specific activated coexisting GPCR of the present invention is group 5-HT4 receptor , GPR101, GPR119, GPR135, GPR137, GPR141, GPR1 49, GPR150, GPR151, GPR152, GPR157, GPR19, GPR 25, GPR37, GPR37L1, GPR50, GPR62, LGR5, MRGPRE MRGPRF, NTS2 receptor, OPN4, OPN4, OR10A7, OR10AG1 , OR10Q1, OR10W1, OR12D3, OR13C2, OR13C3, OR13 C4, OR13C5, OR13C8, OR13F1, OR13G1, OR1A2, OR1 L1, OR1S1, OR1S2, OR2AK2, OR2D2, OR2D3, OR4A15 , OR4C11, OR4C12, OR4C13, OR4C15, OR4C16, OR4K 13, OR4K14, OR4K15, OR4K17, OR4N5, OR5AC2, OR5 AK2, OR5AP2, OR5AR1, OR5AS1, OR5B12, OR5B17, O R5B2, OR5B21, OR5B3, OR5D13, OR5D14, OR5D16, O R5D18, OR5F1, OR5I1, OR5J2, OR5K3, OR5L1, OR5L 2, OR5M1, OR5M10, OR5M11, OR5M3, OR5M8, OR5M9, OR5R1, OR5T1, OR5T2, OR5T3, OR5W2, OR6C74, OR6 K6, OR6M1, OR6Q1, OR6X1, OR8H1, OR8H2, OR8H3, O R8J1, OR8J3, OR8K1, OR8K3, OR8K5, OR8U1, OR8U8 , OR9A4, OR9G1, OR9G4, OR9G9, OR9Q2, TAAR3, TPR A1, Y4 receptor, 5-HT1D receptor, 5-HT1E receptor, ADGRB1, AT2 receptor Receptors, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor, CRF2 receptor ETA receptor, ETB receptor, FZD4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1, GABAB2, GAL1 receptor, GIP receptor, GL P-1 receptor, GLP-2 receptor, glucagon receptor, GnRH2 receptor, GPER, G PR107, GPR139, GPR156, GPR158, GPR161, GPR171 , GPR179, GPR39, GPR45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 receptor, LPA1 receptor, LPA3 receptor, LPA 4 receptors, MC2 receptor, MC4 receptor, mGlu2 receptor, mGlu3 receptor, motil NK2 receptor, MRGPRD, MRGPRX1, MRGPRX3, NK2 receptor, NPFF1 Receptors, NPFF2 receptor, NPS receptor, NTS1 receptor, OR1D2, OR2AG1 OT receptor, PAC1 receptor, RXFP1 receptor, secretin receptor, TSH receptor, UT receptor, V1A receptor, V2 receptor, α2A-adrenergic receptor, α2B-adrenergic receptor Narin receptor, α2C-adrenergic receptor, β1-adrenergic receptor, β3-adrenergic receptor Narin receptor, 5-HT1B receptor, 5-HT1F receptor, 5-HT2B receptor, 5-H T2C receptor, 5-HT5A receptor, 5-HT6 receptor, 5-HT7 receptor, ADGRE 4P, ADGRF1, ADGRG1, ADGRG3, ADGRG5, Calcitonin receptor Receptors such as CB1 receptor, CB2 receptor, CCK1 receptor, CCK2 receptor, and CT receptor D1 receptor, D2 receptor, D3 receptor, D4 receptor, D5 receptor, FFA1 receptor, F FA3 receptor, FSH receptor, FZD1, FZD2, FZD3, GHRH receptor, GnR H1 receptor, GPBA receptor, GPR1, GPR119, GPR12, GPR142, G PR143, GPR146, GPR148, GPR153, GPR160, GPR162 , GPR17, GPR173, GPR174, GPR176, GPR18, GPR182 , GPR20, GPR22, GPR26, GPR27, GPR3, GPR33, GPR3 5, GPR6, GPR61, GPR78, GPR82, GPR83, GPR84, GPR 85, GPR87, GPRC5D, GPRC6 receptor, HCA2 receptor, HCA3 receptor , cyspeptin receptor, LGR4, LGR6, LH receptor, LPA2 receptor, LPA6 receptor Condition, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1L, M C3 receptor, MC5 receptor, MCH2 receptor, mGlu4 receptor, mGlu7 receptor, m Glu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1, OR2A2, OR2A4, OR2A42, OR2 A7, OR2B11, OR2B6, OR2C1, OR2C3, OR2J3, OR2L13 , OR2T11, OR2T34, OR2W3, OR3A3, OR4D10, OR4M1, OR4Q3, OR51A2, OR51A4, OR51A7, OR51B2, OR51B4 , OR51B5, OR51B6, OR51D1, OR51E1, OR51E1, OR51 E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51I1, OR 51I2, OR51J1, OR51L1, OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, OR52A1, OR52A4, OR52A5, OR52B 2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR5 2E5, OR52E6, OR52E8, OR52H1, OR52I1, OR52I2, O R52J3, OR52K1, OR52K2, OR52L1, OR52M1, OR52N1 , OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56 A1, OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR 6V1, OR7D2, OR9A2, oxoglutarate receptor, P2RY10, P2RY8 P2Y12 receptor, P2Y4 receptor, PrRP receptor, QRFP receptor, RXFP2 receptor Condition, RXFP4 receptor, sst1 receptor, sst2 receptor, sst3 receptor, sst4 Receptors, sst5 receptor, TA1 receptor, TAAR2, TAAR5, TAAR6, TAA R8, TAAR9, TAS1R1, TAS1R2, TAS1R3, TAS2R1, TAS 2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS 2R20, TAS2R3, TAS2R30, TAS2R31, TAS2R38, TAS2 R39, TAS2R4, TAS2R40, TAS2R41, TAS2R42, TAS2R 43, TAS2R45, TAS2R46, TAS2R5, TAS2R50, TAS2R6 0, TAS2R7, TAS2R8, TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor Receptor, Y5 receptor, α1A-adrenergic receptor, α1B-adrenergic receptor, α1D - Adrenergic receptor, δ receptor, 5-HT1A receptor, 5-HT2A receptor, A1 receptor Body, A2A receptor, A2B receptor, A3 receptor, ACKR1, ACKR2, ACKR3, ACKR4, ADGRE1, ADGRE2, ADGRE3, ADGRE5, Aperin receptor Body, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT1 receptor BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, C CR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1, CXCR1, CXC R2, CXCR3, CXCR4, CXCR5, CXCR6, CysLT1 receptor, Cys LT2 receptor, DP1 receptor, DP2 receptor, EP1 receptor, EP2 receptor, EP3 receptor Body, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1, FPR2 / ALX, FPR2 / ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, Ghrelin receptors, GPR132, GPR15, GPR18, GPR183, GPR21, GPR31, GPR32, GPR34, GPR4, GPR55, GPR55, GPR65 GPR68, H1 receptor, H2 receptor, H4 receptor, IP receptor, LPA5 receptor, M AS1, MC1 receptor, MCH1 receptor, mGlu1 receptor, mGlu5 receptor, MRG PRX2, MT1 receptor, MT2 receptor, NK1 receptor, NK3 receptor, NMU1 receptor OXE receptor, P2Y1 receptor, P2Y11 receptor, P2Y13 receptor, P2Y14 receptor Receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor, PAR1, PAR2, PAR3 PAR4, PKR1, PKR2, S1P1 receptor, S1P2 receptor, S1P3 receptor, S1P4 receptor, S1P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, V Selected from PAC2 receptor, XCR1, β2-adrenergic receptor, κ receptor, and μ receptor. It is a GPCR.

[0148] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group of paragraphs [000124] in the international publication of the application.

[0149] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group of paragraphs [000124] in the international publication of the application.

[0150] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000124] in the International Publication of this Application, It's CR.

[0151] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5, Except for CCR10 and CXCR3, paragraph [000124] of the International Publication of this Application It is a GPCR selected from the group ].

[0152] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR8, CCR10, CXCR1, CXCR3, CX CR6, CXCR7, dopamine D2 receptor, glucagon-like peptide receptor 1, neuro Tensin NTS2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, Prostaglandin E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor Except for the somatostatin 3 receptor, paragraph

[00012] of the International Publication of this Application It is a GPCR selected from group 4.

[0153] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR4, CCR5, CCR8, CCR10, CXCR 1. CXCR3, CXCR6, CXCR7, dopamine D2 receptor, glucagon-like peptide Prostaglandin receptor 1, neurotensin NTS2 receptor, platelet-activating factor receptor, prostaglandin Prostaglandin E2 receptor, prostaglandin E3 receptor, prostaglandin E4 receptor, Except for the matostatin 1 receptor and somatostatin 3 receptor, the international publication of this application is available. It is a GPCR selected from the group in paragraph [000124].

[0154] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the condition, CCR3 and M2 receptor, paragraph

[0001] of the International Publication of this Application It is a GPCR selected from group

[24] .

[0155] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR4 and M2 receptors, paragraphs in the International Publication of this Application This is a GPCR selected from the group [000124].

[0156] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR5, and M2 receptors, paragraphs in the International Publication of this Application This is a GPCR selected from the group [000124].

[0157] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, and M2, the international publication of this application is included in the following: It is a GPCR selected from the group in paragraph [000124].

[0158] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Apelin receptor, CCR3, CCR8, CC R10, CXCR1, CXCR3, CXCR6, CXCR7, dopamine D2 receptor, Lucagon-like peptide receptor 1, M2 receptor, neurotensin NTS2 receptor, platelet activity Sexualization factor receptor, prostaglandin E2 receptor, prostaglandin E3 receptor, pro Excluding staglandin E4 receptors, somatostatin 1 receptors, and somatostatin 3 receptors Then, a GPCR selected from the group in paragraph [000124] of the International Publication of this Application be.

[0159] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, CCR10, CXCR3 and M2 receptors , a GPCR selected from the group in paragraph [000124] of the International Publication of this Application ru.

[0160] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Aperin receptor, CCR3, CCR4, CC R5, CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Do Pamine D2 receptor, glucagon-like peptide receptor 1, M2 receptor, neurotensin NT S2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin Din E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor and somatos Excluding the tatin 3 receptor, from the group of paragraphs [000124] in the international publication of this application This is the GPCR that is selected.

[0161] In one embodiment, the specific activated coexisting GPCR of the present invention is a group 5-HT1D receptor. Body, 5-HT1E receptor, ADGRB1, AT2 receptor, BB1 receptor, BB3 receptor, CGRP receptor, CRF1 receptor, CRF2 receptor, ETA receptor, ETB receptor, FZ D4, FZD5, FZD7, FZD8, FZD9, GABAB receptor, GABAB1, G ABAB2, GAL1 receptor, GIP receptor, GLP-1 receptor, GLP-2 receptor, G Lucagon receptor, GnRH2 receptor, GPER, GPR107, GPR139, GPR1 56, GPR158, GPR161, GPR171, GPR179, GPR39, GPR 45, GPR88, GPRC5A, GPRC5B, GPRC5C, H3 receptor, HCA1 Receptors, LPA1 receptor, LPA3 receptor, LPA4 receptor, MC2 receptor, MC4 receptor Body, mGlu2 receptor, mGlu3 receptor, motilin receptor, MRGPRD, MRGPR X1, MRGPRX3, NK2 receptor, NPFF1 receptor, NPFF2 receptor, NPS receptor Condition, NTS1 receptor, OR1D2, OR2AG1, OT receptor, PAC1 receptor, RX FP1 receptor, secretin receptor, TSH receptor, UT receptor, V1A receptor, V2 receptor Body, α2A-adrenergic receptor, α2B-adrenergic receptor, α2C-adrenergic Receptors, β1-adrenergic receptor, β3-adrenergic receptor, 5-HT1B receptor, 5-HT1F receptor, 5-HT2B receptor, 5-HT2C receptor, 5-HT5A receptor, 5-HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1, ADGRG1, ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 receptor Body, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 receptor Body, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSH receptor, FZD 1. FZD2, FZD3, GHRH receptor, GnRH1 receptor, GPBA receptor, GPR 1, GPR119, GPR12, GPR142, GPR143, GPR146, GPR1 48, GPR153, GPR160, GPR162, GPR17, GPR173, GPR 174, GPR176, GPR18, GPR182, GPR20, GPR22, GPR2 6, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61, GPR7 8, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D, G PRC6 receptor, HCA2 receptor, HCA3 receptor, kispeptin receptor, LGR4, L GR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 Receptors, M4 receptor, M5 receptor, MAS1L, MC3 receptor, MC5 receptor, MCH2 Receptors, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NO P receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2A1 , OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6, O R2C1, OR2C3, OR2J3, OR2L13, OR2T11, OR2T34, OR 2W3, OR3A3, OR4D10, OR4M1, OR4Q3, OR51A2, OR51 A4, OR51A7, OR51B2, OR51B4, OR51B5, OR51B6, OR 51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR51L 1, OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, OR5 2A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6, O R52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52E8 , OR52H1, OR52I1, OR52I2, OR52J3, OR52K1, OR52 K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N4, OR 52N5, OR52R1, OR52W1, OR56A1, OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR6V1, OR7D2, OR9A2, O Xoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst1 receptor Condition, SST2 receptor, SST3 receptor, SST4 receptor, SST5 receptor, TA1 receptor Body, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1R1, T AS1R2, TAS1R3, TAS2R1, TAS2R10, TAS2R13, TAS2 R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R 30, TAS2R31, TAS2R38, TAS2R39, TAS2R4, TAS2R4 0, TAS2R41, TAS2R42, TAS2R43, TAS2R45, TAS2R4 6, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, T AS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, α1A adrenergic receptor Phosphate receptor, α1B-adrenergic receptor, α1D-adrenergic receptor, δ receptor, 5 -HT1A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A 3 receptors: ACKR1, ACKR2, ACKR3, ACKR4, ADGRE1, ADGR E2, ADGRE3, ADGRE5, Apelin receptor, AT1 receptor, B1 receptor, B2 Receptors, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor, C 5a1 receptor, C5a2 receptor, CaS receptor, CCR1, CCR10, CCR2, CC R3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, Merine receptor, CX3CR1, CXCR1, CXCR2, CXCR3, CXCR4, CX CR5, CXCR6, CysLT1 receptor, CysLT2 receptor, DP1 receptor, DP2 Receptors, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor, FP receptor, FPR1, FPR2 / ALX, FPR2 / ALX, FPR 3. FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GP R15, GPR18, GPR183, GPR21, GPR31, GPR32, GPR34 GPR4, GPR55, GPR65, GPR68, H1 receptor, H2 receptor Body, H4 receptor, IP receptor, LPA5 receptor, MAS1, MC1 receptor, MCH1 receptor Body, mGlu1 receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor Body, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P 2Y11 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor Body, PAF receptor, PAR1, PAR2, PAR3, PAR4, PKR1, PKR2, S 1P1 receptor, S1P2 receptor, S1P3 receptor, S1P4 receptor, S1P5 receptor, Shanate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1, β2-A It is a GPCR selected from drainaneous receptors, κ receptors, and μ receptors.

[0162] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000138] of the international publication of the application.

[0163] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000138] of the international publication of the application.

[0164] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000138] in the International Publication of this Application, It's CR.

[0165] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5, Except for CCR10 and CXCR3, paragraph [000138] of the International Publication of this Application It is a GPCR selected from the group ].

[0166] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR8, CCR10, CXCR1, CXCR3, CX CR6, CXCR7, dopamine D2 receptor, glucagon-like peptide receptor 1, platelet activity Sexualization factor receptor, prostaglandin E2 receptor, prostaglandin E3 receptor, pro Excluding staglandin E4 receptors, somatostatin 1 receptors, and somatostatin 3 receptors Then, a GPCR selected from the group in paragraph [000138] of the International Publication of this Application be.

[0167] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR4, CCR5, CCR8, CCR10, CXCR 1. CXCR3, CXCR6, CXCR7, dopamine D2 receptor, glucagon-like peptide Prostaglandin receptor 1, platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin Din E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor and somatos Excluding the tatin 3 receptor, from the group of paragraphs [000138] in the international publication of this application This is the GPCR that is selected.

[0168] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the condition, CCR3 and M2 receptor, paragraph

[0001] of the International Publication of this Application It is a GPCR selected from group

[38] .

[0169] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR4 and M2 receptors, paragraphs in the International Publication of this Application This is a GPCR selected from the group [000138].

[0170] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR5, and M2 receptors, paragraphs in the International Publication of this Application This is a GPCR selected from the group [000138].

[0171] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, and M2, the international publication of this application is included in the following: It is a GPCR selected from the group in paragraph [000138].

[0172] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Apelin receptor, CCR3, CCR8, CC R10, CXCR1, CXCR3, CXCR6, CXCR7, dopamine D2 receptor, Lucagon-like peptide receptor 1, M2 receptor, neurotensin NTS2 receptor, platelet activity Sexualization factor receptor, prostaglandin E2 receptor, prostaglandin E3 receptor, pro Excluding staglandin E4 receptors, somatostatin 1 receptors, and somatostatin 3 receptors Then, a GPCR selected from the group in paragraph [000138] of the International Publication of this Application be.

[0173] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, CCR10, CXCR3 and M2 receptors , a GPCR selected from the group in paragraph [000138] of the International Publication of this Application ru.

[0174] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Aperin receptor, CCR3, CCR4, CC R5, CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Do Pamine D2 receptor, glucagon-like peptide receptor 1, M2 receptor, neurotensin NT S2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin Din E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor and somatos Excluding the tatin 3 receptor, from the group of paragraphs [000138] in the international publication of this application This is the GPCR that is selected.

[0175] In one embodiment, the specific activated coexisting GPCR of the present invention is group 5-HT1B receptor Body, 5-HT1F receptor, 5-HT2B receptor, 5-HT2C receptor, 5-HT5A receptor Body, 5-HT6 receptor, 5-HT7 receptor, ADGRE4P, ADGRF1, ADGRG 1. ADGRG3, ADGRG5, calcitonin receptor-like receptor, CB1 receptor, CB2 Receptors, CCK1 receptor, CCK2 receptor, CT receptor, D1 receptor, D2 receptor, D3 Receptors, D4 receptor, D5 receptor, FFA1 receptor, FFA3 receptor, FSH receptor, F ZD1, FZD2, FZD3, GHRH receptor, GnRH1 receptor, GPBA receptor, G PR1, GPR119, GPR12, GPR142, GPR143, GPR146, GP R148, GPR153, GPR160, GPR162, GPR17, GPR173, G PR174, GPR176, GPR18, GPR182, GPR20, GPR22, GP R26, GPR27, GPR3, GPR33, GPR35, GPR6, GPR61, GP R78, GPR82, GPR83, GPR84, GPR85, GPR87, GPRC5D GPRC6 receptor, HCA2 receptor, HCA3 receptor, kispeptin receptor, LGR4 LGR6, LH receptor, LPA2 receptor, LPA6 receptor, M1 receptor, M2 receptor, M3 receptor, M4 receptor, M5 receptor, MAS1L, MC3 receptor, MC5 receptor, MC H2 receptor, mGlu4 receptor, mGlu7 receptor, mGlu8 receptor, MRGPRG, NOP receptor, NPBW1 receptor, NPBW2 receptor, OPN3, OR11H1, OR2 A1, OR2A2, OR2A4, OR2A42, OR2A7, OR2B11, OR2B6 , OR2C1, OR2C3, OR2J3, OR2L13, OR2T11, OR2T34, OR2W3, OR3A3, OR4D10, OR4M1, OR4Q3, OR51A2, OR 51A4, OR51A7, OR51B2, OR51B4, OR51B5, OR51B6, OR51D1, OR51E1, OR51E1, OR51E2, OR51F1, OR51F 2, OR51G1, OR51G2, OR51I1, OR51I2, OR51J1, OR5 1L1, OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, O R52A1, OR52A4, OR52A5, OR52B2, OR52B4, OR52B6 , OR52D1, OR52E2, OR52E4, OR52E5, OR52E6, OR52 E8, OR52H1, OR52I1, OR52I2, OR52J3, OR52K1, OR 52K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR56A1, OR56A3, OR56A 4, OR56A5, OR56B1, OR56B4, OR6V1, OR7D2, OR9A2 , oxoglutarate receptor, P2RY10, P2RY8, P2Y12 receptor, P2Y4 receptor Condition, PrRP receptor, QRFP receptor, RXFP2 receptor, RXFP4 receptor, sst 1 receptor, sst2 receptor, sst3 receptor, sst4 receptor, sst5 receptor, TA1 Receptors: TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAS1R1 , TAS1R2, TAS1R3, TAS2R1, TAS2R10, TAS2R13, TA S2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS 2R30, TAS2R31, TAS2R38, TAS2R39, TAS2R4, TAS2 R40, TAS2R41, TAS2R42, TAS2R43, TAS2R45, TAS2 R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8 , TAS2R9, TRH1 receptor, Y1 receptor, Y2 receptor, Y5 receptor, α1A-ad Renaline receptors, α1B-adrenergic receptors, α1D-adrenergic receptors, δ receptors , 5-HT1A receptor, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor A3 receptor, ACKR1, ACKR2, ACKR3, ACKR4, ADGRE1, AD GRE2, ADGRE3, ADGRE5, Apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor C5a1 receptor, C5a2 receptor, CaS receptor, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2 , chemerin receptor, CX3CR1, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CysLT1 receptor, CysLT2 receptor, DP1 receptor, D P2 receptor, EP1 receptor, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor Body, FFA4 receptor, FP receptor, FPR1, FPR2 / ALX, FPR2 / ALX, F PR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR18, GPR183, GPR21, GPR31, GPR32, GPR 34, GPR4, GPR55, GPR55, GPR65, GPR68, H1 receptor, H2 Receptors, H4 receptor, IP receptor, LPA5 receptor, MAS1, MC1 receptor, MCH1 Receptors, mGlu1 receptor, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 Receptors, NK1 receptor, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor P2Y11 receptor, P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 Receptors, PAF receptors, PAR1, PAR2, PAR3, PAR4, PKR1, PKR2 S1P1 receptor, S1P2 receptor, S1P3 receptor, S1P4 receptor, S1P5 receptor succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1, β2 - A GPCR selected from adrenaline receptors, κ receptors, and μ receptors.

[0176] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000152] of the international publication of the application.

[0177] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000152] of the international publication of the application.

[0178] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000152] in the International Publication of this Application, It's CR.

[0179] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5, Except for CCR10 and CXCR3, paragraph [000152] of the International Publication of this Application It is a GPCR selected from the group ].

[0180] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenergic β2 receptor, aperi CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Dopamine D2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, pro Staglandin E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor and Except for the somatostatin 3 receptor, paragraph [000152] of the International Publication of this Application It is a GPCR selected from the group ].

[0181] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenergic β2 receptor, aperi CCR4, CCR5, CCR8, CCR10, CXCR1, CXCR3, CX CR6, CXCR7, dopamine D2 receptor, platelet-activating factor receptor, prostaglandin Din E2 receptor, prostaglandin E3 receptor, prostaglandin E4 receptor, soma Except for the tostatin 1 receptor and somatostatin 3 receptor, in the international publication of this application It is a GPCR selected from the group in paragraph [000152].

[0182] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the condition, CCR3 and M2 receptor, paragraph

[0001] of the International Publication of this Application It is a GPCR selected from group

[52] .

[0183] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR4 and M2 receptors, paragraphs in the International Publication of this Application This is a GPCR selected from the group [000152].

[0184] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors, CCR3, CCR5, and M2 receptors, paragraphs in the International Publication of this Application This is a GPCR selected from the group [000152].

[0185] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, and M2, the international publication of this application is included in the following: It is a GPCR selected from the group in paragraph [000152].

[0186] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Apelin receptor, CCR3, CCR8, CC R10, CXCR1, CXCR3, CXCR6, CXCR7, dopamine D2 receptor, Lucagon-like peptide receptor 1, M2 receptor, neurotensin NTS2 receptor, platelet activity Sexualization factor receptor, prostaglandin E2 receptor, prostaglandin E3 receptor, pro Excluding staglandin E4 receptors, somatostatin 1 receptors, and somatostatin 3 receptors Then, a GPCR selected from the group in paragraph [000152] of the International Publication of this Application be.

[0187] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the receptors CCR3, CCR4, CCR5, CCR10, CXCR3 and M2 receptors , a GPCR selected from the group in paragraph [000152] of the International Publication of this Application ru.

[0188] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α1A receptor, ad Adrenergic α2A receptor, Adrenergic α2C receptor, Adrenergic β1 receptor, Adrena Phosphate β2 receptor, Adrenaline β3 receptor, Aperin receptor, CCR3, CCR4, CC R5, CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Do Pamine D2 receptor, glucagon-like peptide receptor 1, M2 receptor, neurotensin NT S2 receptor, platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin Din E3 receptor, prostaglandin E4 receptor, somatostatin 1 receptor and somatos Excluding the tatin 3 receptor, from the group of paragraphs [000152] in the international publication of this application This is the GPCR that is selected.

[0189] In one embodiment, a specific activated coexisting GPCR of the present invention is a group 5-HT1A receptor. Body, 5-HT2A receptor, A1 receptor, A2A receptor, A2B receptor, A3 receptor, AC KR1, ACKR2, ACKR3, ACKR4, ADGRE1, ADGRE2, ADGR E3, ADGRE5, Apelin receptor, AT1 receptor, B1 receptor, B2 receptor, BB2 (GRP) receptor, BLT1 receptor, BLT2 receptor, C3a receptor, C5a1 receptor, C5a2 receptor, CaS receptor, CCR1, CCR10, CCR2, CCR3, CCR4 CCR5, CCR6, CCR7, CCR8, CCR9, CCRL2, chemerin receptor, CX3CR1, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXC R6, CysLT1 receptor, CysLT2 receptor, DP1 receptor, DP2 receptor, EP1 Receptors, EP2 receptor, EP3 receptor, EP4 receptor, FFA2 receptor, FFA4 receptor FP receptor, FPR1, FPR2 / ALX, FPR2 / ALX, FPR3, FZD6, GAL2 receptor, GAL3 receptor, ghrelin receptor, GPR132, GPR15, GPR 18, GPR183, GPR21, GPR31, GPR32, GPR34, GPR4, G PR55, GPR55, GPR65, GPR68, H1 receptor, H2 receptor, H4 receptor IP receptor, LPA5 receptor, MAS1, MC1 receptor, MCH1 receptor, mGlu1 Receptors, mGlu5 receptor, MRGPRX2, MT1 receptor, MT2 receptor, NK1 receptor Body, NK3 receptor, NMU1 receptor, OXE receptor, P2Y1 receptor, P2Y11 receptor P2Y13 receptor, P2Y14 receptor, P2Y2 receptor, P2Y6 receptor, PAF receptor Body, PAR1, PAR2, PAR3, PAR4, PKR1, PKR2, S1P1 receptor, S1P2 receptor, S1P3 receptor, S1P4 receptor, S1P5 receptor, succinate receptor, TP receptor, VPAC1 receptor, VPAC2 receptor, XCR1, β2-adrenergic receptor It is a GPCR selected from the somatic receptor, κ receptor, and μ receptor.

[0190] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000166] of the international publication of the application.

[0191] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000166] of the international publication of the application.

[0192] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000166] in the International Publication of this Application, It's CR.

[0193] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5, Except for CCR10 and CXCR3, paragraph [000166] of the International Publication of this Application It is a GPCR selected from the group ].

[0194] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenergic β2 receptor, aperi CCR8, CCR10, CXCR1, CXCR3, CXCR6, CXCR7, Platelet-activating factor receptor, prostaglandin E2 receptor, prostaglandin E3 receptor Except for the body and prostaglandin E4 receptor, paragraph [0 This is a GPCR selected from the group

[00166] .

[0195] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenergic β2 receptor, aperi CCR4, CCR5, CCR8, CCR10, CXCR1, CXCR3, CX CR6, CXCR7, platelet-activating factor receptor, prostaglandin E2 receptor, pros Except for the taglandin E3 receptor and prostaglandin E4 receptor, the international publication of this application It is a GPCR selected from the group in paragraph [000166] of the publication.

[0196] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR3, are The GPCR is selected from the group in paragraph [000166] of the international publication of the application.

[0197] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR3 and CCR4 Except for the GP selected from the group of paragraphs [000166] in the International Publication of this Application, It's CR.

[0198] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR3 and CCR5 Except for the GP selected from the group of paragraphs [000166] in the International Publication of this Application, It's CR.

[0199] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR3, CCR4 and Excluding CCR5, select from the group of paragraphs [000166] in the International Publication of this Application. It is a GPCR.

[0200] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, apelin receptor, CCR3, CCR8, CCR10, CXCR1, CXC R3, CXCR6, CXCR7, dopamine D2 receptor, glucagon-like peptide receptor 1 Neurotensin NTS2 receptor, platelet-activating factor receptor, prostaglandin E2 Receptors, prostaglandin E3 receptor, prostaglandin E4 receptor, somatostat Except for the 1 receptor and the somatostatin 3 receptor, paragraphs in the international publication of this application [ This is a GPCR selected from the group [000166].

[0201] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR3, CCR4, Except for CCR5, CCR10, and CXCR3, paragraphs in the International Publication of this Application [0 This is a GPCR selected from the group

[00166] .

[0202] In one embodiment, a specific activated coexisting GPCR of the present invention is an adenosine A2A receptor Body, adenosine A2B receptor, adenosine A3 receptor, adrenaline α2A receptor, ad Adrenergic α2C receptor, Adrenergic β1 receptor, Adrenergic β2 receptor, Adrenergic β3 receptor, Apelin receptor, CCR3, CCR4, CCR5, CCR8, CCR10 CXCR1, CXCR3, CXCR6, CXCR7, dopamine D2 receptor, glucago Peptide receptor 1, neurotensin NTS2 receptor, platelet-activating factor receptor, Prostaglandin E2 receptor, prostaglandin E3 receptor, prostaglandin E4 Except for the receptors, somatostatin 1 receptor and somatostatin 3 receptor, the international publication of this application This is a GPCR selected from the group in paragraph [000166] of the published patent.

[0203] In one embodiment, the specific activated coexisting GPCR of the present invention includes group:AT1R. Ggiotensin receptors as well as CCR1, CCR2, CCR6, CCR7, CXCR2, C GP selected from specific chemokine receptors, including XCR4, CXCR6, and CXCR7. It's CR.

[0204] In one embodiment, the specific activated coexisting GPCR of the present invention includes group:AT1R. Ggiotensin receptors as well as CCR1, CCR2, CCR6, CCR7, CXCR1, C Selected from specific chemokine receptors including XCR2, CXCR4, CXCR6, and CXCR7 This is the GPCR that will be selected.

[0205] In one embodiment, the specific activated coexisting GPCR of the present invention includes group:AT1R. Ggiotensin receptors as well as CCR1, CCR2, CCR6, CCR7, CXCR1, C GP selected from specific chemokine receptors, including XCR2, CXCR4, and CXCR6. It's CR.

[0206] In one embodiment, the specific activated coexisting GPCR of the present invention includes group:AT1R. Ggiotensin receptors as well as CCR1, CCR2, CCR6, CCR7, CXCR2, C It is a GPCR selected from specific chemokine receptors, including XCR4 and CXCR6.

[0207] In one embodiment, the specific activated coexisting GPCR of the present invention includes group:AT1R. Ggiotensin receptors as well as CCR1, CCR2, CCR6, CCR7, CXCR1, C It is a GPCR selected from specific chemokine receptors, including XCR2 and CXCR6.

[0208] In one embodiment, the specific activated coexisting GPCR of the present invention includes group:AT1R. Ggiotensin receptors and CCR1, CCR2, CCR6, CCR7, CXCR2 and It is a GPCR selected from specific chemokine receptors, including CXCR6.

[0209] In one embodiment, the activated coexisting GPCR of the present invention is vasopressin receptor 2. .

[0210] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE. It is a mokine receptor.

[0211] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR3, CCR4, CCR5, CC R6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR 3. Choose from CXCR4, CXCR5, CXCR6, CXCR7, CX3CR1, XCR1. It is a selected chemokine receptor.

[0212] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR4, CCR6, CC R7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXC Choose from R4, CXCR5, CXCR6, CXCR7, CX3CR1, XCR1. It is a mokine receptor.

[0213] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR5, CCR6, CC R7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXC Choose from R4, CXCR5, CXCR6, CXCR7, CX3CR1, XCR1. It is a mokine receptor.

[0214] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR6, CCR7, CC R8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CX Chemokine receptors selected from CR5, CXCR6, CXCR7, CX3CR1, and XCR1. That is the condition.

[0215] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR6, CCR7, CC R8, CCR9, CXCR1, CXCR2, CXCR4, CXCR5, CXCR6, CX It is a chemokine receptor selected from CR7, CX3CR1, and XCR1.

[0216] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR4, CCR5, CCR6, CC R7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXC Choose from R4, CXCR5, CXCR6, CXCR7, CX3CR1, XCR1. It is a mokine receptor.

[0217] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR4, CCR6, CCR7, CC R8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CX Chemokine receptors selected from CR5, CXCR6, CXCR7, CX3CR1, and XCR1. That is the condition.

[0218] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR5, CCR6, CCR7, CC R8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CX Chemokine receptors selected from CR5, CXCR6, CXCR7, CX3CR1, and XCR1. That is the condition.

[0219] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR6, CCR7, CCR8, CC R9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, C It is a chemokine receptor selected from XCR6, CXCR7, CX3CR1, and XCR1. .

[0220] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR6, CCR7, CCR8, CC R9, CXCR1, CXCR2, CXCR4, CXCR5, CXCR6, CXCR7, C It is a chemokine receptor selected from X3CR1 and XCR1.

[0221] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR6, CCR7, CC R8, CCR9, CXCR1, CXCR2, CXCR5, CXCR6, CXCR7, CX It is a chemokine receptor selected from 3CR1 and XCR1.

[0222] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR6, CCR7, CC R8, CCR9, CXCR2, CXCR4, CXCR5, CXCR6, CXCR7, CX It is a chemokine receptor selected from 3CR1 and XCR1.

[0223] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease and group: CCR1, CCR2, CCR3, CCR6, CCR7, CC R8, CCR9, CXCR2, CXCR5, CXCR6, CXCR7, CX3CR1, X It is a chemokine receptor selected from CR1.

[0224] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR6, CCR7, CCR8, CC R9, CXCR1, CXCR2, CXCR5, CXCR6, CXCR7, CX3CR1, It is a chemokine receptor selected from XCR1.

[0225] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR6, CCR7, CCR8, CC R9, CXCR2, CXCR4, CXCR5, CXCR6, CXCR7, CX3CR1, It is a chemokine receptor selected from XCR1.

[0226] In one embodiment, a specific chemokine receptor is co-expressed in the same cell as RAGE, and flame Related to the disease, and group: CCR1, CCR2, CCR6, CCR7, CCR8, CC From R9, CXCR2, CXCR5, CXCR6, CXCR7, CX3CR1, XCR1 It is a selected chemokine receptor.

[0227] In one embodiment of the present invention, the specific activated coexisting GPCR of the present invention is group: adenosine 1 A receptor, adrenaline α1A receptor, adrenaline α1B receptor, adrenaline α2B receptor Receptors, angiotensin receptor AT1R, bradykinin receptor B2, CCR1, CCR 2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CXCR2, CX CR4, CXCR5, dopamine D1 receptor, endothelin receptor type A, endothelin receptor Type B receptor, histamine H3 receptor, muscarinic M1 receptor, muscarinic M2 receptor, mus Karin M3 receptor, neuropeptide Y1 receptor, neurotensin 1 receptor, orexi 1 receptor, orexin receptor 2, prostaglandin E1 receptor, serotonin 5-HT receptor 1a receptor, serotonin 5-HT2a receptor, serotonin 5-HT2b receptor, serotonin 5-HT2c receptor, serotonin 5-HT4b receptor, somatostatin 2 receptor, sulfonamide Sphingosine 1-phosphate receptor S1P1, sphingosine 1-phosphate receptor S1P3, cy tropin-releasing hormone receptor 1, vasopressin receptor 1A, vasopressin receptor 1B or This is a GPCR selected from vasopressin receptor 2.

[0228] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000204] of the international publication of the application.

[0229] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000204] of the international publication of the application.

[0230] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000204] in the International Publication of this Application, It's CR.

[0231] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5 and Excluding CXCR4, selected from the group of paragraphs [000204] in the International Publication of this Application This is the GPCR that will be selected.

[0232] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, muscarinic M2 receptor, and orexin receptor 1, the international of this application It is a GPCR selected from the group in paragraph [000204] of the published patent application.

[0233] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, CCR4, muscarinic M2 receptor and orexin receptor 1, this The GPCR is selected from the group in paragraph [000204] of the international publication of the application.

[0234] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, CCR5, muscarinic M2 receptor and orexin receptor 1, this The GPCR is selected from the group in paragraph [000204] of the international publication of the application.

[0235] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor The body contains CCR3, CCR4, CCR5, muscarinic M2 receptor and orexin receptor 1. Excluding the GPC selected from the group of paragraphs [000204] in the International Publication of this Application, It is R.

[0236] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, CXCR4, muscarinic M2 receptor and orexin receptor 1, A GPCR selected from the group in paragraph [000204] of the International Publication of this Application. .

[0237] In a preferred embodiment of the present invention, a specific activated coexisting GPCR of the present invention is group:adre Narin α1A receptor, adrenaline α1B receptor, angiotensin receptor AT1R, Radikinin receptors B2, CCR2, CCR3, CCR4, CCR6, CCR9, CXCR 4. CXCR5, dopamine D1 receptor, endothelin receptor type B, histamine H3 receptor Body, muscarinic M2 receptor, neuropeptide Y1 receptor, neurotensin 1 receptor, Orexin receptor 1, orexin receptor 2, prostaglandin E1 receptor, serotonin 5-HT2b receptor, serotonin 5-HT2c receptor, serotonin 5-HT4b receptor, Somatostatin 2 receptor, sphingosine 1-phosphate receptor S1P3, vasopressin receptor It is a GPCR selected from either vasopressin receptor 1A or vasopressin receptor 1B.

[0238] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000214] of the international publication of the application.

[0239] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CXCR Except for 4, G selected from the group of paragraphs [000214] in the International Publication of this Application. It's PCR.

[0240] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, muscarinic M2 receptor, and orexin receptor 1, the international of this application It is a GPCR selected from the group in paragraph [000214] of the published patent application.

[0241] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, CCR4, muscarinic M2 receptor and orexin receptor 1, this The GPCR is selected from the group in paragraph [000214] of the international publication of the application.

[0242] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Condition, CCR3, CCR4, CXCR4, muscarinic M2 receptor and orexin receptor 1 Except for the GP selected from the group of paragraphs [000214] in the International Publication of this Application, It's CR.

[0243] In a particularly preferred embodiment of the present invention, the specific activated coexisting GPCRs of the present invention are group: A α1A receptor for drenaline, α1B receptor for adrenaline, and AT1R receptor for angiotensin , bradykinin receptor B2, CCR2, CCR6, CCR9, CXCR4, CXCR5, Dopamine D1 receptor, endothelin receptor type B, histamine H3 receptor, muscarinic M 2 receptors, neuropeptide Y1 receptor, orexin receptor 1, orexin receptor 2, Rostaglandin E1 receptor, serotonin 5-HT2c receptor, serotonin 5-HT4b receptor Receptors, somatostatin 2 receptor, sphingosine 1-phosphate receptor S1P3, vasopressor It is a GPCR selected from either syn receptor 1A or vasopressin receptor 1B.

[0244] In one embodiment, the specific activated coexisting GPCRs of the present invention, excluding CXCR4, A GPCR selected from the group in paragraph [000220] of the International Publication of this Application. .

[0245] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, muscarinic M2 receptor, and orexin receptor 1, the international of this application It is a GPCR selected from the group in paragraph [000220] of the published patent application.

[0246] In one embodiment, a specific activated coexisting GPCR of the present invention is an adrenaline α1A receptor Except for the pharmacokinetics, CCR3, CXCR4, muscarinic M2 receptor and orexin receptor 1, A GPCR selected from the group in paragraph [000220] of the International Publication of this Application. .

[0247] In one embodiment of the present invention, a specific activated coexisting GPCR of the present invention is group: adenosine A Adrenaline receptor 1 (ADORA1), adrenaline α2B receptor, angiotensin receptor AT1 (AT1R), bradykinin receptor 2 (B2R), CCR1, CCR2, CCR4, CC R5, CCR6, CCR7, CCR9, CXCR2, CXCR4, CXCR5, Neuro Peptide Y1 receptor (NPY1R), orexin receptor 2, sphingosine-1-phosphate receptor Body 1 (S1PR1), thyroid-stimulating hormone-releasing hormone receptor 1 (TRHR1), Vasop Resin receptor 1A (V1aR), vasopressin receptor 1B (V1bR), and vasopressin It is a GPCR selected from receptor 2 (V2R).

[0248] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000224] of the international publication of the application.

[0249] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000224] of the international publication of the application.

[0250] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000224] in the International Publication of this Application, It's CR.

[0251] In one embodiment, the specific activated coexisting GPCRs of the present invention, excluding CXCR4, A GPCR selected from the group in paragraph [000224] of the International Publication of this Application. .

[0252] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5 and Excluding CXCR4, selected from the group of paragraphs [000224] in the International Publication of this Application This is the GPCR that will be selected.

[0253] In a preferred embodiment of the present invention, a specific activated coexisting GPCR of the present invention is group:ad Lenolin α2B receptor, angiotensin receptor AT1 (AT1R), bradykinin receptor Body 2 (B2R), CCR1, CCR2, CCR4, CCR5, CCR6, CCR9, CX CR2, CXCR4, neuropeptide Y1 receptor (NPY1R), orexin receptor 2 , sphingosine-1 phosphate receptor 1 (S1PR1), thyroid-stimulating hormone-releasing hormone receptor Receptor 1 (TRHR1), vasopressin receptor 1A (V1aR), vasopressin receptor 1B It is a GPCR selected from (V1bR) and vasopressin receptor 2 (V2R).

[0254] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR4, are The GPCR is selected from the group in paragraph [000230] of the international publication of the application.

[0255] In one embodiment, the specific activated coexisting GPCRs of the present invention, except for CCR5, are The GPCR is selected from the group in paragraph [000230] of the international publication of the application.

[0256] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4 and CCR5 Except for the GP selected from the group of paragraphs [000230] in the International Publication of this Application, It's CR.

[0257] In one embodiment, the specific activated coexisting GPCRs of the present invention, excluding CXCR4, A GPCR selected from the group in paragraph [000230] of the International Publication of this Application. .

[0258] In one embodiment, the specific activated coexisting GPCRs of the present invention are CCR4, CCR5 and Excluding CXCR4, selected from the group of paragraphs [000230] in the International Publication of this Application This is the GPCR that will be selected.

[0259] In a particular embodiment of the present invention, the activated coexisting GPCR of the present invention is an angiotensin receptor That is the condition.

[0260] In a particular embodiment of the present invention, the activated coexisting GPCR of the present invention is AT1R.

[0261] In a particular embodiment of the present invention, the activated coexisting GPCRs of the present invention are group: CCR1, CC Choose from R2, CCR6, CCR7, CXCR2, CXCR4, CXCR6, and CXCR7. It is a specific chemokine receptor that is selected.

[0262] In a particular embodiment of the present invention, the activated coexisting GPCRs of the present invention are group: CCR1, CC Selected from R2, CCR6, CCR7, CXCR1, CXCR2, and CXCR6. It is a chemokine receptor.

[0263] In a particular embodiment of the present invention, the activated coexisting GPCRs of the present invention are group: CCR1, CC A specific chemokine selected from R2, CCR6, CCR7, CXCR2, and CXCR6. It is a receptor.

[0264] In a particular embodiment of the present invention, the activated coexisting GPCRs of the present invention are CCR2 and CCR It is a specific chemokine receptor selected from 6.

[0265] In a particular embodiment of the present invention, the activated coexisting GPCR of the present invention is CCR2.

[0266] In a particular embodiment of the present invention, the activated coexisting GPCR of the present invention is CXCR4.

[0267] In one embodiment of the present invention, the RAGE ligand interacts with the extracellular domain of RAGE. It is a ligand that modulates RAGE activation. Therefore, in this embodiment of the present invention, RA GE ligand-independent RAGE activation involves interactions with the extracellular domain of RAGE. This refers to the activation of RAGE that does not occur via Gand.

[0268] Preferably, the RAGE ligand interacts with the extracellular domain of RAGE to enhance RAGE It regulates the activation of the transmembrane domain or cytoplasmic tail of RAGE or contained therein. It is a ligand that does not interact with the motif. Therefore, in this preferred embodiment of the present invention RAGE ligand-independent RAGE activation is when the ligand is located in the transmembrane domain of RAGE. Alternatively, unless it interacts with the cytoplasmic tail or the motif contained therein, RAG This means that RAGE activation does not occur via ligands that interact with the extracellular domain of E. do.

[0269] The extracellular domain of RAGE (also called the external domain) consists of three immunoglobulin-like molecules. Region: N-terminal V-type domain followed by two C-type domains (C and C' or alternatively) It includes (referred to as C1 and C2). The main ligand-binding region is the V domain, RAGE activation can also be mediated by ligand binding to the C domain. The ligand is Because they tend to be negatively charged, most ligands have a V domain and / or C1 domain. It tends to bind to the C2 domain, but there is at least one example of a ligand that binds to the C2 domain. S100A6; Leclerc et al., 2007). The C1 and C2 domains are, In general, they may not directly bind to the ligand, but they do interact with the ligand. It may play an important role in stabilizing the V domain for mediation. RAGE It has a single transmembrane domain and a cytoplasmic tail. In humans, the cytoplasmic side of RAGE The tail is 43 amino acids long (residues 362 to 404). This cytoplasmic tail is It contains motifs that are important for RAGE-dependent cell activation.

[0270] In one embodiment of the present invention, the RAGE ligand is the extracellular V, C of the extracellular domain of RAGE. This invention is a ligand that interacts with the 1 and / or C2 domain to activate RAGE. In this form, RAGE ligand-independent RAGE activation is the extracellular domain of RAGE. RA does not occur via ligands that interact with the extracellular V, C1, or C2 domains of rheumatoid arthritis (RA). This means the activation of GE.

[0271] Preferably, the RAGE ligand is the transmembrane domain or cytoplasmic tail of RAGE. or does not interact with the motif contained therein. In this embodiment of the present invention, RAGE rig ligand-independent RAGE activation occurs when the ligand is present in the transmembrane domain or cytoplasm of RAGE. Unless it interacts with the lateral tail or the motif contained therein, RAGE extracellular inhibitory effect RA does not occur via ligands that interact with the extracellular V, C1, or C2 domains of rheumatoid arthritis (RA). This means the activation of GE.

[0272] In one embodiment of the present invention, activated angiotensin receptors such as AT1R or CCR2, etc. , regulating RAGE ligand-independent RAGE activation by activated coexisting GPCRs. The modulator also modulates the RAGE ligand-dependent activation of RAGE.

[0273] In a preferred embodiment of the present invention, the modulator of the present invention is a specific activated coexistence It does not regulate, or modulates differently, the RAGE-independent signaling pathway associated with GPCRs. To modify or adjust to a different degree.

[0274] In a preferred embodiment, the modulator of the present invention comprises one or more RAGE-independent features It does not inhibit, or inhibits less than, certain coexisting GPCR signaling pathways.

[0275] In one embodiment of the present invention, a specific coexisting GPCR signaling pathway independent of RAGE is G This is a q signaling pathway. In one embodiment of the present invention, a specific coexisting GPC independent of RAGE. The R signaling pathway is the Gi / o signaling pathway. In one embodiment of the present invention, RAG The specific coexisting GPCR signaling pathway that is E-independent is the Gs signaling pathway. In one embodiment of the invention, a specific coexisting GPCR signaling pathway independent of RAGE is used. This is a signaling pathway. In one embodiment of the present invention, a specific coexisting GP independent of RAGE. The CR signaling pathway is the phospholipase C signaling pathway. Another embodiment of the present invention So, what are the specific coexisting GPCR signaling pathways that are RAGE-independent? This is extracellular regulatory kinase (ERK) signaling.

[0276] In a particularly preferred embodiment, the activated coexisting GPCR is activated AT1R. The modulator of the present invention modulates one or more RAGE-independent AT1R signaling pathways. Do not adjust, or adjust to a smaller extent.

[0277] In a particularly preferred embodiment, the activated coexisting GPCR is activated AT1R. The modulator of the present invention modulates one or more RAGE-independent AT1R signaling pathways. It inhibits or inhibits to a lesser extent.

[0278] In one embodiment of the present invention, the RAGE-independent AT1R signaling pathway is a Gq signaling pathway. This is the signaling pathway. In another embodiment of the present invention, the RAGE-independent AT1R signaling pathway is This is β-arrestin-mediated extracellular regulatory kinase (ERK) signaling.

[0279] Another particularly preferred embodiment is that the activated coexisting GPCR is activated CCR2. Therefore, the modulator of the present invention is used in one or more RAGE-independent CCR2 signaling pathways. Do not adjust the road, or adjust it to a lesser extent.

[0280] Another particularly preferred embodiment is that the activated coexisting GPCR is activated CCR2. Therefore, the modulator of the present invention is used in one or more RAGE-independent CCR2 signaling pathways. To not obstruct the road, or to obstruct it to a lesser extent.

[0281] In one embodiment of the present invention, the RAGE-independent AT1R signaling pathway is a Gi / o signaling pathway. This is a signaling pathway. In another embodiment of the present invention, the RAGE-independent CCR2 signaling pathway This is β-arrestin-mediated extracellular regulatory kinase (ERK) signaling. Another aspect of the present invention Morphologically, the RAGE-independent CCR2 signaling pathway is a phospholipase C signaling pathway. This is the route.

[0282] <Modulator> In one embodiment of the present invention, the modulator of the present invention is an activator, inhibitor, allosteric It is a functional or non-functional substitute for the modulator or the cytoplasmic tail of RAGE. The active substitute is a module that replaces the cytoplasmic tail of RAGE in the presence of certain coexisting GPCRs. It is an activator, which is activated by them, in the presence or absence of wild-type RAGE expression. It can induce downstream RAGE-dependent signaling. Non-functional alternatives are, It is a modulator that replaces the cytoplasmic tail of RAGE in the presence of certain coexisting GPCRs. , or they cannot be activated by them, or downstream RAGE-dependent signal propagation They could not be induced, and the activation of the cytoplasmic tail of RAGE and the resulting It inhibits signal transduction that normally occurs through RAGE-dependent signaling.

[0283] In one embodiment of the present invention, the modulator of the present invention is an activator, inhibitor, allosteric A non-functional substitute for the modulator or the transmembrane domain or part thereof of RAGE. .

[0284] Non-functional substitutes are modulators that replace the transmembrane domain of RAGE in the presence of specific co-existing GPCRs and cannot be activated by them, or cannot induce downstream RAGE-dependent signaling, and inhibit the signaling that normally occurs through the activation of the cytoplasmic tail of RAGE and the resulting RAGE-dependent signaling. In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof and a fragment of the extracellular domain of RAGE. In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof and a fragment of the cytoplasmic tail of RAGE. In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof, a fragment of the extracellular domain of RAGE, and a fragment of the cytoplasmic tail of RAGE. In one form of the invention, the modulator of the invention contains a fragment of the extracellular domain of RAGE that is 40 amino acids or less in length, 20 amino acids or less in length, 10 amino acids or less in length, or 5 amino acids or less in length.

[0285] As an example of a modulator, the inventors have found that RAGE is a functional substitute for RAGE and can be activated by specific co-existing GPCRs such as AT1R and CCR2, and can, in the presence or absence of the expression of wild-type RAGE, be independent of RAGE ligands.

[0286] In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof and a fragment of the extracellular domain of RAGE. In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof and a fragment of the cytoplasmic tail of RAGE.

[0287] In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof, and a fragment of the extracellular domain of RAGE, and a fragment of the cytoplasmic tail of RAGE. In one form of the invention, the modulator of the invention contains a fragment of the extracellular domain of RAGE that is 40 amino acids or less in length, 20 amino acids or less in length, 10 amino acids or less in length, or 5 amino acids or less in length.

[0288] In one form of the invention, the modulator of the invention contains a fragment of the extracellular domain of RAGE that is 40 amino acids or less in length, 20 amino acids or less in length, 10 amino acids or less in length, or 5 amino acids or less in length. In one form of the invention, the modulator of the invention contains a fragment of the extracellular domain of RAGE that is 40 amino acids or less in length, 20 amino acids or less in length, 10 amino acids or less in length, or 5 amino acids or less in length. In one form of the invention, the modulator of the invention contains a fragment of the extracellular domain of RAGE that is 40 amino acids or less in length, 20 amino acids or less in length, 10 amino acids or less in length, or 5 amino acids or less in length.

[0289] As an example of a modulator, the inventors have found that RAGE is a functional substitute for RAGE and can be activated by specific co-existing GPCRs such as AT1R and CCR2, and can, in the presence or absence of the expression of wild-type RAGE, 362-404 be independent of RAGE ligands. In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof and a fragment of the extracellular domain of RAGE. In one form of the invention, the modulator comprises the transmembrane domain of RAGE or a portion thereof and a fragment of the cytoplasmic tail of RAGE. It was found that the presence of RAGE activation induces downstream RAGE-dependent signaling. He proved it. Furthermore, RAGE 362-404 Cell permeable peptide (TAT) and marker When fused to the protein (mCherry), it leads to activation of AT1R by Ang II. TAT-mCherry-RAGE 362-404 Treatment with oligopeptides is wild In the absence of RAGE expression, Ang II in AGER / apoE-DKO mice It can reverse dependent inflammation and atheroma formation.

[0290] RAGE 362-404 The array is sequence number 1. [ka]

[0291] As an example of adding a modulator, the inventors have introduced S391A-RAGE 362-40 4 is not activated by certain coexisting GPCRs, and RAGE-dependent signaling It was demonstrated to be a non-functional substitute for RAGE, which inhibits NAL transmission. S391A-RA GE 362-404 Expression is independent of wild-type RAGE ligand by activated AT1R. RAGE activation and RAGE ligand S100A8 / A9 activating wild-type RAGE It inhibits E-ligand-dependent activation. Furthermore, S391A-RAGE 362-404 Thin When fused to the vesicular permeable peptide (TAT) and the marker protein (mCherry), TAT-mCherry-S391A-RAGE 362-404 Treatment by oligopeptides This inhibits RAGE ligand-independent RAGE activation by activated AT1R. Therefore, Ang II-dependent inflammation and ate in apolipoprotein E knockout mice It reduces loam formation. Further examples are provided below.

[0292] S391A-RAGE 362-404 The array is sequence number 2. [ka]

[0293] As another example of a modulator, the inventors of RAGE 338-361 However, activation A We demonstrated that T1R inhibits wild-type RAGE ligand-independent RAGE activation. This inhibition is mCherry-RAGE 362-404 This is overcome by co-expression. .

[0294] RAGE 338-361 The sequence is sequence number 3. [L 338 GTLALALGILGGLGTAALLIGVI 361 ]

[0295] In one embodiment, the present invention relates to angiotensin receptors such as AT1R or CCR2, etc. Activation of certain activated coexisting GPCRs, such as chemokine receptors, triggers Specific activated It includes a modulator of RAGE ligand-independent RAGE activation by coexisting GPCRs. nothing.

[0296] In one embodiment, the present invention relates to protein kinase C zeta (PKCζ), Dock7, MyD88, TIRAP, IRAK4, ERK1 / 2, olfactory receptor 2T2, ADP / AT P-translocase 2, protein phosphatase 1G, intercellular adhesion molecule 1, protein DJ-1 (PARK7), Carponin-3, Drebrin, Filamin B, Ras-related tannins Protein Rab-13, Radixin / Ezrin / Moesin, Proteolipid Protein 2 , Coronin, S100 A11, succinyl-CoA ligase [GDP formation] subunit Tα, Hsc70 interacting protein, apoptosis inhibitor 5, neuropilin, cutting stab Stimulant factor, growth factor receptor-binding protein 2, sec61β subunit, or Nck1 Ras-GTPase activation-like protein (IQGAP1) or other RAG It binds to E-related proteins, or to angiotensin receptors such as AT1R or C RAGE is triggered by specific activated coexisting GPCRs, such as chemokine receptors like CR2. To regulate Lance activation, certain activations disrupt the binding of these elements to RAGE. RAGE ligand-independent activity of the cytoplasmic tail of RAGE by sexualized coexisting GPCRs Includes a modulator for sexualization.

[0297] In one embodiment of the present invention, the modulator of the present invention is IQGAP-1, PKCζ, Doc k7, MyD88, TIRAP, IRAK4, ERK1 / 2, olfactory receptor 2T2, ADP / ATP translocase 2, protein phosphatase 1G, intercellular adhesion molecule 1, tan Protein DJ-1 (PARK7), Carponin-3, Drebrin, Filamin B, Ras-related Linked protein Rab-13, radixin / ezrin / moesin, proteolipid protein Substrate 2, Coronin, S100 A11, Succinyl-CoA ligase [GDP formation] sub Unit α, Hsc70 interacting protein, apoptosis inhibitor 5, neuropilin, Severance stimulant, growth factor receptor-binding protein 2, sec61β subunit or N Cytosolic elements of certain activated coexisting GPCRs, including ck1, RAGE and / or It binds to elements that are complexed with either of them, such as angiotensin receptors like AT1R, Alternatively, it may be due to specific activated coexisting GPCRs, such as chemokine receptors like CCR2. By regulating these signaling elements necessary for RAGE transactivation, RA It regulates RAGE ligand-independent signaling via the cytoplasmic tail of GE.

[0298] In one embodiment of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulator of RAGE activation is the cytosolic element and / or cytoso Elements that combine with RAGE (IQGAP-1, PKCζ, Dock7, MyD88, I RAK4, TIRAP, ERK1 / 2, olfactory receptor 2T2, ADP / ATP translocator -ase 2, protein phosphatase 1G, intercellular adhesion molecule 1, protein DJ-1 (PA RK7), carponin-3, drebrin, filamin B, Ras-related protein Rab- 13. Radixin / Ezrin / Moesin, Proteolipid Protein 2, Coronin, S 100 A11, succinyl-CoA ligase [GDP formation] subunit α, Hsc7 0 Interacting proteins, apoptosis inhibitors, neuropilins, cleavage stimulants, growth factors It binds to receptor-binding proteins (such as sec61β subunit or Nck1). This also modulates the RAGE ligand-dependent activation of the cytoplasmic tail of RAGE, These elements inhibit RAGE ligand-mediated signaling.

[0299] In certain embodiments, the modulator is the amino acid sequence described in Sequence ID No. 1 or a similar sequence. It includes, consists of, or is essentially composed of, analogues, fragments, or derivatives.

[0300] In some embodiments, the modulator is used for gene delivery (electroporation, Microinjection, gene gun, impalefect Ion, hydrostatic pressure, continuous injection, sonication, lipofection, liposomes, nanobubbles and polymer gene carriers, etc., are used for the delivery of viruses or artificial nonviral genes. Introduced by (such as by) peptide fragments, biologically active analogs or Derivatives are produced by cells as a result of transcription and translation processes.

[0301] In some embodiments of this model, the modulator is such as AT1R or CCR2. Modified ability to form complexes with specific coexisting GPCRs or elements that combine with them. It has, for example, a RAGE analog or derivative has at least one amino acid residue substitution. , addition or deletion or addition of abnormal or non-conventional amino acids or non-amino acid residues This can be distinguished from wild-type RAGE polypeptides or fragment sequences by substitution.

[0302] In some embodiments, the modulator is typically used with wild-type human RAGE polypeptide. The present serine 391 lacks or has the modification. In this exemplary example, Fragments, analogs, or derivatives of the cytoplasmic tail of RAGE are located at position 391 of the wild-type RAGE sequence. Lacking serine (for example, RAGE 370-390 The structure was cut with Glu390. (It is done). Appropriately, the serine at position 391 is used after activation of the coexisting GPCR. Is it deleted in a way that impairs or disables the signaling mediated by phosphorus? , or substituted with another amino acid residue, analog, or derivative. In one embodiment, 391 Serine at this position is either missing or in the group: alanine, aspartic acid, phenylalanine histidine, lysine, arginine, tyrosine, asparagine, valine, glycine, cis It is substituted with another amino acid residue selected from theine or glutamic acid.

[0303] In some embodiments, the modulator is typically used with wild-type human RAGE polypeptide. It either retains the existing serine 391, or another that retains the same function as serine at position 391. It is substituted with an amino acid or its analog or derivative. In this type of example, The cytoplasmic tail fragment of RAGE retains the serine at position 391 of the wild-type RAGE sequence. (For example, RAGE 370-404 (Construction). Appropriately, serine at position 391 is this The signature is conferred after activation of coexisting GPCRs by a RAGE construct containing serine at the site. In order to replicate the signal, it is substituted with another amino acid residue or its analog or derivative. In one embodiment, the serine at position 391 is in the group: proline, glutamine, threonine. , or another amino acid selected from leucine, isoleucine, methionine, or tryptophan It is substituted with a residue.

[0304] In some embodiments, the modulator diaps compared to human wild-type RAGE. It lacks or has reduced ability to bind to hanous 1 (Diaph1). In this type of exemplary example, the peptide or its analogues, fragments, or derivatives are RAG E-Diaph1 binding site (RAGE 370-390 , RAGE 374-390 or RA GE 379-390 (etc.) are lacking, or are altered in a way that disables or impairs this part. It has a Diaph1 binding site (366A / 367A, etc.). Appropriately, 366 / 367 residues have been deleted in such a way that they impair or disable this site, or other It is substituted with a residue (such as alanine), which allows the wild type to bind to Diaph1. By reducing the constraints caused by [the aforementioned factor], the affinity for binding to other targets is improved. .

[0305] In one aspect of the present invention, the modulator of the present invention is defined by formula I: Z1 M Z2 (I) (In the formula, Z1 is either absent or contains a small proteinous portion consisting of approximately 1 to 50 amino acid residues. At least one will be selected; M is the amino acid sequence described in Sequence ID No. 1, or an analog, fragment, or derivative thereof; and Z2 is either absent or a proteinaceous moiety containing approximately 1 to 50 amino acid residues. ) A single amino acid sequence that includes, consists of, or is essentially derived from, the amino acid sequence represented by Contains separated or purified peptides.

[0306] In some embodiments of the present invention described above, a modulator (as described above and in other parts of this specification) (The fragments of the cytoplasmic tail of RAGE, its analogues, or derivatives, etc., are widely described in [location].) It can permeate the cell membrane. In a non-limiting example of this type, RAGE Module The molecule is a cell membrane permeable molecule (for example, the HIV-TAT motif described in Sequence ID No. 4 below). ) is conjugated, fused, or otherwise linked.

[0307] Sequence ID 4: [YGRKKRRQRRR].

[0308] In some embodiments of the present invention, the modulator is used to target specific activated coexisting GPCRs. It binds to and / or interferes with elements related to RAGE activation that are RAGE ligand-independent. These are non-peptide molecules that share the ability to modify peptides with the peptide modulators mentioned above. Peptide modulators target functionally important domains within peptide modulators. There may or may not be structural similarities between them.

[0309] In a preferred embodiment, the non-peptide modulator is as described in the International Publication of this Application. As represented by the pharmacophore described in paragraph [000318], the peptide modifier This includes functionally important domains and structural similarities within the regulator.

[0310] In a preferred embodiment of the present invention, the modulator is an inhibitor.

[0311] In certain embodiments of the present invention, RAGE ligand non-activation by specific activated coexisting GPCRs In addition to being an inhibitor of RAGE-dependent activation, the modulator is a specific coexisting G It is a PCR inhibitor and / or an inhibitor of a specific coexisting GPCR signaling pathway.

[0312] In certain embodiments of the present invention, RAGE ligand non-activation by specific activated coexisting GPCRs In addition to being an inhibitor of RAGE-dependent activation, the modulator is R of RAGE. Inhibitors of AGE ligand-dependent activation, and / or inhibitors of constitutively active RAGE, / or it is an inhibitor of the RAGE signaling pathway.

[0313] In a particular embodiment of the present invention, where the specific coexisting GPCR is AT1R, RAGE ligand-independent In addition to being an inhibitor of RAGE activation, the modulator is an AT1R inhibitor. It is an inhibitor of the AT1R signaling pathway.

[0314] In certain embodiments of the present invention, an activated angiotensin receptor, preferably an activated AT1R receptor, is used. In addition to being a RAGE ligand-independent inhibitor of RAGE activation, the module The inhibitor is an inhibitor of RAGE ligand-dependent activation and / or constitutive activity of RAGE. It is an inhibitor of type RAGE and / or an inhibitor of the RAGE signaling pathway.

[0315] In certain embodiments of the present invention, RAGE ligand non-activation by specific activated coexisting GPCRs In addition to being an inhibitor of RAGE-dependent activation, the modulator is a specific coexisting G A PCR inhibitor and / or an inhibitor of a specific coexisting GPCR signaling pathway, RAG Inhibitors of RAGE ligand-dependent activation of E, and / or inhibitors of constitutively active RAGE. It is an inhibitor of the RAGE signaling pathway.

[0316] In certain embodiments of the present invention, an activated angiotensin receptor, preferably an activated AT1R receptor, is used. In addition to being a RAGE ligand-independent inhibitor of RAGE activation, the module The inhibitor is an AT1R inhibitor and / or an inhibitor of the AT1R signaling pathway, RA Inhibitors of RAGE ligand-dependent activation of GE, and / or inhibition of constitutively active RAGE. It is a drug and / or an inhibitor of the RAGE signaling pathway.

[0317] The present invention is characterized in that a specific coexisting GPCR is a specific chemokine receptor, preferably CCR2. In its standard form, in addition to being a RAGE ligand-independent inhibitor of RAGE activation, The modulator is a specific chemokine receptor inhibitor, preferably a CCR2 inhibitor and / Or an inhibitor of a specific chemokine signaling pathway, preferably the CCR2 signaling pathway. That is the case.

[0318] In certain embodiments of the present invention, an activated specific chemokine receptor, preferably activated C110, is used. In addition to being an inhibitor of CR2-mediated RAGE ligand-independent RAGE activation, Modulators are inhibitors of RAGE ligand-dependent activation and / or components of RAGE. It is an inhibitor of the active form of RAGE, and / or an inhibitor of the RAGE signaling pathway.

[0319] In certain embodiments of the present invention, activated chemokine receptors, preferably activated CCR2, are In addition to being a RAGE ligand-independent inhibitor of RAGE activation, it is also a modulator. - A specific chemokine receptor inhibitor, preferably a CCR2 inhibitor and / or a specific chemokine Inhibitors of the Caine signaling pathway, preferably the CCR2 signaling pathway, and RAG Inhibitors of RAGE ligand-dependent activation of E, and / or inhibitors of constitutively active RAGE. It is an inhibitor of the RAGE signaling pathway.

[0320] In a particular embodiment of the present invention, the modulator is the cytoplasmic tail or a portion thereof of RAGE. It is a functional substitute for certain coexisting GPCRs such as activated AT1R and activated CCR2. Therefore, it can be activated, and downstream RA in the presence or absence of wild-type RAGE expression It induces GE-dependent signaling.

[0321] In a particular embodiment of the present invention, the modulator is the cytoplasmic tail or a portion thereof of RAGE. It is a non-functional substitute, and the non-functional substitute is activated by coexisting GPCRs. It is either not possible, or it is not possible to promote downstream RAGE-dependent signaling, and RAGE cells It inhibits signaling that occurs through quality tails and RAGE-dependent signaling.

[0322] In a particular embodiment of the present invention, the modulator is the transmembrane domain of RAGE or a portion thereof. It is a non-functional substitute, and the non-functional substitute is activated by coexisting GPCRs. It is either not possible, or it is not possible to promote downstream RAGE-dependent signaling, and RAGE cells It inhibits signaling that occurs through quality tails and RAGE-dependent signaling.

[0323] In a particular embodiment of the present invention, the modulator is the transmembrane domain of RAGE or a portion thereof. and fragments of the extracellular domain of RAGE. In certain embodiments of the present invention, modulator This includes the transmembrane domain of RAGE or a portion thereof and a fragment of the cytoplasmic tail of RAGE. .

[0324] In a particular embodiment of the present invention, the modulator is the transmembrane domain of RAGE or a portion thereof. This includes a fragment of the extracellular domain of RAGE, and a fragment of the cytoplasmic tail of RAGE.

[0325] In certain embodiments of the present invention, RAGE ligand non-activation by specific activated coexisting GPCRs The modulators of RAGE activation that are dependent on RAGE activation are those with a length of 40 amino acids or less, and 20 amino acids or less. Below is the ligand-binding exostructure of human wild-type RAGE, which has 10 amino acids or less or 5 amino acids or less. It contains domain fragments.

[0326] The inventors have identified a peptide containing residues 370-390 of the cytoplasmic tail of RAGE (sequence). (See number 5) However, wild-type RAGE ligand-independent RAGE activation and RAG We further discovered that it is an inhibitory peptide that inhibits both E ligand-dependent activation and E ligand-dependent activation.

[0327] Sequence ID 5: [G 370 EERKAPENQEEEEERAELNQ 390 ].

[0328] RAGE 363-404 Regarding the existence of solution NMR structures (Rai V et a (1., 2012), the N-terminus of this peptide (residues 363-376) is ordered. This is indicated. RAGE- 362-404 (Model 4) Rosetta-derived model It exists and matches the NMR structure (http: / / www.rcsb.org / pdb / e xplore / explore.do?structureId=2LMB, 2016 (Accessed August 25) It also suggests that the remaining part of the peptide forms an α-helix. It is.

[0329] RAGE 370-390 The initial model was the Model 4 (Model 4_ 370-390 ) cut It was built by disconnecting. Model 4 is the I-Tasser Web server (ht tp: / / zhanglab.ccmb.med.umich.edu / I-TASSE A theoretical model of the cytoplasmic tail of RAGE, generated by inputting the sequence into R / ). This is according to Yang et al (2015), Roy et al (2010), and Y See also Zhang (2008). (Provided by the I-Tasser server) All five models predicted that region 370-390 would form a helix. The NMR structure was aligned by the Cα carbon of the peptide sequence backbone. Di Model 4 The predicted structure of the region corresponding to the aphanous 1 binding site was recorded for this region. Model 4 was selected as the preferred model because it most closely matched the NMR structure.

[0330] Using GROMACS, we performed a 20ns molecular dynamics simulation of Model 4 in water. This was performed (Hess et al., 2008). Molecular dynamics simulations are model 4_ 370-390 This suggests that the α-helix region is stable. Numerous charges Strong interactions were observed between the side chains, and these interactions stabilize the folded structure. This suggests that the arbitrary preservation of these residues may be due to their role in stabilizing the peptide structure. This suggests that...

[0331] Using Blast search, RAGE 370-390 Homologous sequences were identified. The sequences are as follows: It was aligned like this. CLUSTAL 2.0.10 Multiple Array Alignment [ka] [ka] [ka]

[0332] Based on this analysis, RAGE was marked as follows: 370-390 Numerous in Strongly conserved residues were identified. * (asterisk) indicates a single, completely conserved residue. The colon (:) indicates the conservation of groups with strongly similar properties. (Gonnet PAM 250 matrix score > 0.5). (period) This shows conservation between groups with weakly similar properties (Gonnet PAM 250 matrix). Score in the game = <0.5).

[0333] [Table 24]

[0334] Highly conserved residues may play a structural role. Underlined residues are It is located on one face of the helix and may represent a binding pharmacophore.

[0335] Model 4_RAGE 370-390 We examined the results of structural and molecular dynamics simulations. This reveals that numerous salt bridges exist within the structure. Molecular dynamics simulations This indicates that these interactions are important structural features. Structural function is these meshes This is a possible reason for the conserved properties of ano acids.

[0336] Many strongly conserved amino acids are not involved in salt bridge formation. These are RAGE 370-390 It exists on one side of the helix and may represent a bonding interface. These are Glu380, Glu384, Glu387, and Leu388. Another high The conserved residue Glu377 is also present on this side of the peptide and is linked to Lys374. In addition to forming α-helix-stabilized salt bridges, it can also be involved in binding.

[0337] Alanine at the major hydrophobic residue L388 (e.g., L388A-RAGE) 370-390 ) substitution, when it acts on wild-type RAGE, 370-390 Achieved by This results in a loss of inhibition of the N-terminal transistor of RAGE, which eliminates both 380 and 384. Kate (for example, RAGE 385-390 and RAGE 385-404 ) are these R This results in a loss of regulatory action of AGE constructs. In contrast, it eliminates both 374 and 377. The N-terminal truncate of RAGE is an inhibitor (RAGE 379-390 ) as or wild Functional alternatives to type RAGE (e.g., RAGE 379-404 ) as RAGE Peptide This does not result in a loss of function of the nucleotide, because these conserved residues (374 and 377) In cases where it can play a role in stabilizing the α-helical tertiary structure of the cytoplasmic tail of RAGE This also indicates that it is not essential for regulatory activity.

[0338] The inventors have determined that, in accordance with the conserved properties of these four amino acids representing the bonding surface, RA A peptide containing only residues 379-390 of the cytoplasmic tail of GE (i.e., RAGE) 37 9-390 ) However, the ligand-independent activation and ligand-dependent activation of wild-type RAGE It is an inhibitory peptide that inhibits both and RAGE 379-404 In CHO cells, We further discovered that it can be activated by a specific coexisting GPCR.

[0339] In a preferred embodiment of the present invention, an angiotensin receptor such as AT1R or CCR2, etc. RAGE liganization by specific activated coexisting GPCRs, such as specific chemokine receptors. The RAGE activation-independent modulator is E-peptide Q, as described in SEQ ID NO: 6. 37 9EEEEERAELNQ 390 or a derivative thereof.

[0340] Sequence ID 6: [Q 379 EEEEERAELNQ 390 ]

[0341] Structural Model 4_RAGE 370-390 RAGE 379-390 Peptides The pharmacophores are shown below. [ka]

[0342] H4 is a hydrophobic residue, P1-P3 are polar residues, and the distance is angstrom. It is represented by M. The matrix of distances between points is as follows, where P is polarity. The term represents a site (hydrogen bond or charge), where H represents a hydrophobic site. The distance is measured in angstroms. It is a system. Tolerances should be applied to the position of each point.

[0343] [Table 25]

[0344] Molecular dynamics simulations are performed using RAGE. 379-390 The interacting group is mobile, If the magnitude of the distance between sites is positive, a tolerance of up to ±10 Å should be applied to the position of each base. This indicates that...

[0345] As those skilled in the art will understand, by taking the above subset, an additional smaller F Pharmacophores can be generated, and the present invention relates to such pharmacophores, compounds This includes such methods of use for identifying compounds and compounds thus identified.

[0346] In one embodiment, the present invention relates to the group: first charged or hydrogen bonding group (A), second charged or Selected from hydrogen bonding group (B), third charged or hydrogen bonding group (C), and hydrophobic group (D) RAGE ligand independence by specific activated coexisting GPCRs, including two or more features. Further including a modulator of RAGE activation, the distance between feature sites is the site point If the magnitude of the distance between them is positive, within a tolerance of up to ±10 Å, the following applies: be.

[0347] [Table 26]

[0348] In a preferred embodiment of the present invention, when the magnitude of the distance between points is positive, the tolerance is maximum It is ±5 Å. In a preferred embodiment of the present invention, when the magnitude of the distance between site points is positive, it is permissible. The tolerance is a maximum of ±2 Å. In a preferred embodiment of the present invention, the magnitude of the distance between site points is positive. In some cases, the tolerance is a maximum of ±1 Å.

[0349] In a preferred embodiment of the present invention, the modulator is selected from the group identified above. It includes more than one of the following features.

[0350] In a preferred embodiment of the present invention, the modulator has four features from the group identified above. Includes.

[0351] In one embodiment of the present invention, one of the following combinations: AB, AC, AD, BC, BD, and CD A modulator is provided that includes at least two features selected from ru.

[0352] In one embodiment of the present invention, one of the following combinations: ABC, ABD, ACD, and BCD A modulator is provided that includes at least three selected features.

[0353] In one embodiment of the present invention, the following combinations: at least four selected from one of A, B, C, and D A modulator is provided that includes the following features.

[0354] In one embodiment of the present invention, the modulator is RAGE 370-390 The preservation of E377 It contains additional charged or hydrogen-bonding groups (P1) that are consistent with the stabilizing effect, and therefore, the group : First charged or hydrogen bonding group (A), second charged or hydrogen bonding group (B), third charged Alternatively, selected from a hydrogen bonding group (C), a fourth charged or hydrogen group (D), and a hydrophobic group (E). A modulator is provided which includes two or more features, and the distance between the feature points The separation is as follows, within a tolerance of ±10 Å:

[0355] [Table 27]

[0356] [ka] RAGE ligand-independent RAGE activation modulators include peptides or non-peptide molecules. It could be a tidyl compound.

[0357] In one embodiment of the present invention, the hydrophobic group is one of the following groups: Ala, Val, Leu, Ile, Phe, T This is an amino acid residue selected from rp and Tyr.

[0358] In one embodiment of the present invention, the hydrophobic group is group:C 1~8 Alkyl, C 1~8 Alkenil, C3 ~6 Cycloalkyl, aryl, substituted aryl, alkylaryl, heteroaryl, a This is the chemical part selected from lucyl heteroaryl.

[0359] "Alkyl" refers to an aliphatic hydrocarbon group, which can be linear or branched, with approximately one such group per chain. It contains approximately 20 carbon atoms. Preferred alkyl groups have approximately 1 to 12 carbon atoms in the chain. Includes. Preferred alkyl groups contain about 1 to 6 carbon atoms in the chain. Branched chains contain methyl One or more lower alkyl groups, such as ethyl or propyl, are bonded to the linear alkyl chain. It means that.

[0360] A "lower alkyl" is a linear or branched chain containing approximately 1 to 6 carbon atoms. It means a group that performs an action. Alkyl groups are one or more groups that are either identical or different by arbitrary choice. The substituents may be halo, alkyl, aryl, cycloalkyl, or shea substituents. No, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(silicone) Composed of chloroalkyl, -N(alkyl)2, carboxy, and -C(O)O-alkyl groups. Selected independently from the group. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n - Contains propyl, isopropyl, and t-butyl.

[0361] "Alkenyls" can be straight-chain or branched-chain, and each chain contains approximately 2 to 15 carbon atoms. , meaning an aliphatic hydrocarbon group containing at least one carbon-carbon double bond. Preferred A The lukenyl group has approximately 2 to 12 carbon atoms in the chain, more preferably 2 to 4 carbon atoms in the chain. It has carbon atoms. The branched chain is made of one or more lower aluminum atoms such as methyl, ethyl, or propyl. This means that the kill group is bonded to a linear alkenyl chain.

[0362] A "lower alkenyl" is a chain that can be straight or branched, containing approximately 2 to 6 carbon atoms. This means that. Non-restrictive examples of suitable alkenyl groups include ethenyl, propenyl, and 2-butene. This includes nyl and 3-methylbutenyl. The term "substituted alkenyl" refers to alkenyl. This means that the group can be substituted with one or more substituents that are either identical or different, and each substitution The group is independently selected from the group consisting of alkyl, aryl, and cycloalkyl groups.

[0363] "Alkynnyl" can be a straight or branched chain, and each chain contains approximately 2 to 15 carbon atoms. , meaning an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. Preferred A The lukinyl group has approximately 2 to 12 carbon atoms in the chain, more preferably 2 to 4 carbon atoms in the chain. It has carbon atoms. The branched chain is one or more lower alkyl groups such as methyl, ethyl, or propyl. This means that the alkynyl group is bonded to a straight alkynyl chain.

[0364] A "lower alkynyl" is a chain that can be straight or branched, containing approximately 2 to 6 carbon atoms. This means that. Non-restrictive examples of suitable alkynyl groups include ethynyl, propynyl, and 2-butyric. This includes yl and 3-methylbutynyl. The term "substituted alkynyl" refers to alkynyl. This means that the group can be substituted with one or more substituents that are either identical or different, and each substitution The group is independently selected from the group consisting of alkyl, aryl, and cycloalkyl groups.

[0365] "Aliphatic" refers to paraffins, olefins, or acetylene carbon atoms in a straight or branched chain. The aliphatic groups may be identical or different, depending on the choice of one or more groups. It can be substituted with substituents, each substituent being H, halo, halogen, alkyl, or aryl. cycloalkyl, cycloalkylamino, alkenyl, heterocycle, alkynyl, cyclo Lukylaminocarbonyl, hydroxyl, thio, cyano, hydroxyl, alkoxy, aldehyde Kilthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2) Carboxyl, -C(O)O-alkyl, heteroaryl, aralkyl, alkyl Lille, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroarkenyl hydroxyalkyl, aryloxy, aryloxy Acyl, aroyl, nitro, amino, amide, ester, aryl carboxylate Rubonyl, Aralkoxycarbonyl, Alkylsulfonyl, Arylsulfonyl, Hetero Arylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroaryls Rufinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, hete Roaralkyrthio, cycloalkenyl, heterocyclyl, heterocyclinyl, carbame Urea, ketones, aldehydes, cyanoamides, sulfonamides, sulfoxides, sulfones Rufonylurea, sulfonyl, hydrazide, hydroxamate, S(alkyl)Y1Y2N -alkyl-, Y1Y2N-alkyl-, Y1Y2NC(O)-, and Y1Y2NSO2- Independently selected from the group consisting of, where Y1 and Y2 may be the same or different. , independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl.

[0366] "Heteroaliphatic" refers to a compound containing at least one heteroatom (such as oxygen, nitrogen, or sulfur). It means that, in other respects, it is an aliphatic group. The term heteroaliphatic means substitution It includes heteroaliphatic species.

[0367] "Aryl" is a carbon atom with approximately 6 to 14 carbon atoms, preferably approximately 6 to 10 carbon atoms. This refers to an aromatic monocyclic or polycyclic ring system containing aryl groups. The aryl groups may be the same or different. It may be optionally substituted with one or more "ring substituents" as defined herein. It is possible. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. It can be done.

[0368] "Heteroalkyl" refers to a heteroatom in which one or more hydrogen atoms are selected from N, S, or O. This refers to the alkyl group defined above, which is substituted with [the specified character].

[0369] A "heteroaryl" consists of approximately 5 to 14 ring atoms, preferably approximately 5 to 10 ring atoms. This refers to an aromatic monocyclic or polycyclic ring system containing ring atoms, where one or more ring atoms are noncarbon. The elements are, for example, nitrogen, oxygen, or sulfur, either alone or in combination. Preferred heterogeneity A heteroaryl compound contains approximately 5 to 6 ring atoms. "Heteroaryl" is either identical or different. The obtained can be optionally replaced with one or more "ring substituents" as defined herein. It is possible. The prefix aza, oxa, or thia before the root name of a heteroaryl is This means that at least one nitrogen, oxygen, or sulfur atom exists as a ring atom. The nitrogen atom of loaryl can be optionally oxidized to the corresponding N-oxide. Appropriate heteroaryl non-exclusive examples include pyridyl, pyrazinyl, furanil, and thie. Nyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isoth Azolyl, Oxazolyl, Thiazolyl, Pyrazolyl, Flazanyl, Pyrrolyl, Pyrazolyl Triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridadinyl, quinoxali Nyl, phthalazinyl, oxyindolyl, imidazo[1,2-a]pyridinyl, imidazo [2,1-b] Thiazolyl, Benzoflazanil, Indolyl, Azaindolyl, Benzu Midazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl Lu, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzo This includes zaindolyl, 1,2,4-triazinyl, and benzothiazolyl. The term "aryl" is used, for example, in tetrahydroisoquinolyl, tetrahydroquinolyl This refers to any saturated heteroaryl moiety.

[0370] "Aralkyl" or "arylalkyl" is defined as aryl and alkyl as described above. This refers to an aryl-alkyl group. Preferred aralkyl groups include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl, and naphthalenylmethyl. It contains til. The bond to the parent part is via alkyl.

[0371] "Alkylaryl" is an alkyl-aryl compound where alkyl and aryl are as described above. It means a group. Preferred alkylaryls include lower alkyl groups. A non-restrictive example of a aryl group is the toryl. Bonding to the parent moiety is via the aryl group.

[0372] "Cycloalkyl" has about 3 to about 10 carbon atoms, preferably about 5 to about 10 This refers to a non-aromatic monocyclic or polycyclic ring system containing carbon atoms. Preferred cycloalkyl rings are It contains approximately 5 to 7 ring atoms. The cycloalkyl groups may be the same or different as described above. It can be optionally substituted with one or more "ring substituents" as defined in [the relevant section]. Suitable non-limiting examples of monocyclic cycloalkyls include cyclopropyl and cyclopentyl. This includes cyclohexyl, cycloheptyl, etc. A suitable polycyclic cycloalkyl is available indefinitely. Typical examples include 1-decalinyl, norbornyl, adamantyl, and, for example, indani. This includes partially saturated species such as fluorine and tetrahydronaphthyl. "Halogens" include fluorine and chlorine. This refers to bromine or iodine. Fluorine, chlorine, and bromine are preferred.

[0373] A "cyclic substituent" is, for example, an aromatic or non-aromatic substituent that replaces an available hydrogen atom on the ring system. This refers to substituents bonded to a ring system. Ring substituents may be the same or different, each Alkyl, Alkenyl, Alkinyl, Aryl, Heteroaryl, Aralkyl, Alky Heteroaryl, Heteroarylalkynyl, Heteroarylalkenyl, Heteroarylalkynyl , alkyl heteroaryl, hydroxy, hydroxyalkyl, alkoxy, arylo Xy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alcohol Cicarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, he Telalylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterosyl Krill, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH (alkyl), Y1Y2N-, Y1Y2N-alkyl-, Y1Y2NC(O)-, Y1Y Independently selected from the group consisting of 2NSO2- and -SO2NY1Y2, where Y1 and Y2 may be the same or different, hydrogen, alkyl, aryl, cycloalkyl and It is independently selected from the group consisting of aralkyls. A "ring substituent" is two in the ring system. It simultaneously replaces two available hydrogen atoms on adjacent carbon atoms (one H on each carbon). It can also mean a single part. An example of such a part is the following: Examples include methylenedioxy, ethylenedioxy, and -C(CH3)2-. [ka]

[0374] In the heteroatom-containing ring system of the present invention, a hydroxyl atom is located on a carbon atom adjacent to N, O, or S1. It should be noted that there is no N group, and there is no N or S group on the carbon adjacent to another heteroatom. Therefore, for example, in a ring, [ka] There are no -OH groups directly bonded to the carbons labeled 2 and 5.

[0375] For example, the chemistry part: [ka] Other tautomers, such as those mentioned above, are considered equivalents in certain embodiments of the present invention. Please be mindful.

[0376] "Alkynylalkyl" is a compound where alkynyl and alkyl are as described above. This refers to an alkyl group. Preferred alkynylalkyls are lower alkynyl and lower alkynyl groups. Contains a kill group. Bonding to the parent moiety is via an alkyl group. Suitable alkynylalkyl group A limited example is propargylmethyl.

[0377] "Heteroaryl" is a heteroaryl and alkyl compound as described above. This refers to an alkyl group. Preferred heteroalkyl groups include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinoline-3-ylmethyl. It contains [a specific component]. The bond to the parent part is via an alkyl group.

[0378] "Hydroxyalkyl" is defined as HO-alkyl- group, where alkyl is defined as previously defined. This means that preferred hydroxyalkyls include lower alkyls. Non-limiting examples of the lukyl group include hydroxymethyl and 2-hydroxyethyl.

[0379] "Acyl" refers to HC(O)-, alkyl-C(O)-, or cycloalkyl-C(O) - This refers to a group, and the various groups are as described above. The bond to the parent part is via a carbonyl group. Preferred acyls include lower alkyls. Non-limiting examples of suitable acyl groups include holmi It contains acetyl and propanoyl.

[0380] "Aroyl" refers to the aryl-C(O)- group, as described above. The bond to the parent group is via a carbonyl group. Non-limiting examples of suitable groups include benzoyl and It contains 1-naphthoyl.

[0381] "Alkoxy" refers to an alkyl-O-group, as described above. (Appropriate) Non-exclusive examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy. It contains xy and n-butoxy. Binding to the parent moiety is via ether oxygen.

[0382] "Aryloxy" refers to the aryl-O- group, which is defined as the aryl group mentioned above. Suitable non-limiting examples of aryloxy groups include phenoxy and naphthoxy. Binding to the portion occurs via ether oxygen.

[0383] "Alkylthio" refers to the alkyl-S-group, as described above. Non-limiting examples of the alkylthio group include methylthio and ethylthio. The bond to is via sulfur.

[0384] "Arylthio" refers to the aryl-S-group, as described above. Non-limiting examples of the arylthio group include phenylthio and naphthylthio. Bonding to the part is via sulfur.

[0385] "Aralkylthio" refers to the aralkyl-S- group, as described above. A suitable non-restrictive example of an aralkylthio group is benzylthio. The bond to the parent moiety is , via sulfur.

[0386] "Alkoxycarbonyl" refers to an alkyl-O-CO- group. Non-limiting examples of carbonyl groups include methoxycarbonyl and ethoxycarbonyl groups. The bond to the parent molecule is via a carbonyl group.

[0387] "Aralkoxycarbonyl" means an aralkyl-OC(O)- group. A non-restrictive example of the ralcoxycarbonyl group is benzyloxycarbonyl. (To the parent part) The bond is mediated by a carbonyl group.

[0388] "Alkylsulfonyl" means an alkyl-S(O2)- group. The preferred group is A The alkyl group is a lower alkyl group. The bond to the parent moiety is via a sulfonyl group.

[0389] "Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent part is , via sulfonyl.

[0390] The term "substitution" refers to a substitution that does not exceed the normal valence of the specified atom in its current state, and is stable. When a compound is formed, one or more hydrogen atoms on a specified atom are selected from the specified group. This means that it is replaced by. The combination of substituents and / or variables is such a combination This is only permissible if the combination results in a stable compound.

[0391] "Stable compounds" or "stable structures" are isolated from reaction mixtures to a useful purity and have This refers to a compound that is strong enough to withstand formulation into an effective therapeutic agent.

[0392] The term "replaced by arbitrary selection" means that a particular group, radical, or part is replaced by an arbitrary selection of a specific group, radical, or part. This means substitution by choice.

[0393] When a functional group in a compound is referred to as "protected," it means that the compound is not subjected to reaction. When used, the group is modified to prevent undesirable side reactions at the protected site. This means that appropriate protecting groups are recognized by those skilled in the art, and also, for example, Greene This can be recognized by referring to standard texts such as et al (1991). It is likely.

[0394] Any component or any variable in the present invention (e.g., aryl, heteroalgebra, R²) If a term appears multiple times, its definition in each occurrence is the same as its definition in all other occurrences. They are independent entities.

[0395] In one embodiment of the present invention, each charged or hydrogen bonding group is independently of the groups Asp and Glu. These are amino acid residues that are selected.

[0396] In one embodiment of the present invention, each of the charged or hydrogen bonding groups is an amine having a carboxylic acid moiety. It is an acid residue.

[0397] In one embodiment of the present invention, each of the charged or hydrogen bonding groups is from the group: carboxylic acid, hydroxyl Acids, phosphonic acids and phosphinic acids, sulfonic acids and sulfinic acids, sulfonamides, acid Sulfonamides and sulfonylureas, 2,2,2-trifluoroethane-1-ol and Trifluoromethyl ketone, tetrazole, 5-oxo-1,2,4-oxadiazole Lu and 5-oxo-1,2,4-thiadiazole, thiazolidinedione, oxazolidine Dione and oxadiazolidinedione-dione, 3-hydroxyisoxazole and 3-hydro Xyisothiazole, substituted phenol, squalane, 3- and 4-hydroxyquinoline -2-one, tetranic acid and tetramic acid, cyclopentan-1,3-dione and boron Contains acids, mercaptoazoles, and sulfonimidamide (Ballatore et al.) (2013) It is a chemical moiety selected independently from other cyclic and acyclic structures.

[0398] In one embodiment, the present invention relates to angiotensin receptors such as AT1R or CCR2. RAGE ligand non-reactive by specific activated coexisting GPCRs, such as certain chemokine receptors. A method is provided for identifying modulators of dependent RAGE activation, and the method is: (1) The three-dimensional structure of the compound is defined by the group: first charged or hydrogen bonding group (A), second charged or Selected from hydrogen bonding group (B), third charged or hydrogen bonding group (C), and hydrophobic group (D) A step of comparing a pharmacophore containing two or more features, wherein the distance between features is Within a tolerance of ±10 Å, the following steps are observed:

[0399] [Table 28] (2) Having a hydrophobic and / or charged or hydrogen-bonding chemical part arranged in such a manner The process includes the step of selecting a compound.

[0400] RAGE ligand-independent identified by the above methods, including comparison with pharmacophores. The modulator of RAGE activation can be a peptide or a non-peptidyl compound. .

[0401] In a preferred embodiment of the present invention, when the magnitude of the distance between points is positive, the tolerance is maximum It is ±5 Å. In a preferred embodiment of the present invention, when the magnitude of the distance between site points is positive, it is permissible. The tolerance is a maximum of ±2 Å. In a preferred embodiment of the present invention, the magnitude of the distance between site points is positive. In some cases, the tolerance is a maximum of ±1 Å.

[0402] In a preferred embodiment of the present invention, the modulator is selected from the group identified above. It includes more than one of the following features.

[0403] In a preferred embodiment of the present invention, the modulator has four features from the group identified above. Includes.

[0404] In one embodiment of the present invention, the comparison between the three-dimensional structure of a compound and its pharmacophore is the most important aspect of the compound. This involves a comparison between low-energy structures and pharmacophores.

[0405] An efficient means of selecting a compound from a potentially large number of compounds is the three-dimensional chemical structure of the compound. To screen one or more computerized databases, Using a computer program, for example Catalyst (MSl), the pharmaceutical of the present invention This includes comparing cophores with compounds.

[0406] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The RAGE activation modulator has the amino acid sequence described in Sequence ID No. 1. A ptide or an analog, fragment, or derivative thereof containing at least residues 379-390 be.

[0407] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The modulator of RAGE activation is the peptide or analog of the formula in SEQ ID NO: 1. It is either a derivative or a derivative.

[0408] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The modulator of RAGE activation is the peptide or analog of the formula in Sequence ID No. 2. It is either a derivative or a derivative.

[0409] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The modulator of RAGE activation is the peptide or analog of the formula in SEQ ID NO: 5. It is either a derivative or a derivative.

[0410] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The modulator of RAGE activation is the peptide or analog of the formula of SEQ ID NO: 6. It is either a derivative or a derivative.

[0411] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The modulator for RAGE activation in existence is S391A-E392X, as described in Sequence ID 7. - RAGE peptide or its analogues or derivatives.

[0412] Sequence ID 7: [L 362 WQRRQRRGEERKAPENQEEEEERAELNQA 391 ]

[0413] In one embodiment of the present invention, an angiotensin receptor such as AT1R or a specific receptor such as CCR2 is used. RAGE ligand-independent chemokine receptors and other specific activated coexisting GPCRs The modulator for RAGE activation is S391X-RAGE, as described in Sequence ID No. 8. It is a butylate or an analog or derivative thereof.

[0414] Sequence ID 8: [L 362 WQRRQRRGEERKAPENQEEEEERAELNQ 390 ]

[0415] A preferred specific derivative is Q as described in Sequence ID No. 9 below. 379 EEEEERAELNR 390 Q as described in Sequence ID No. 10 379 EEEEERAELNK 390 , in sequence number 11 K as described 379 EEEEERAELNQ 390 , K as described in Sequence ID No. 12 379 EEEE RAELNK 390 and K described in Sequence ID No. 13 379 EEEEERAELNR 390 of include. Sequence ID 9: [Q 379 EEEEERAELNR 390 ] Sequence ID 10: [Q 379 EEEEERAELNK 390 ] Sequence ID 11:[K 379 EEEEERAELNQ 390 ] Sequence ID 12:[K 379 EEEEERAELNK 390 ] Sequence ID 13:[K 379 EEEEERAELNR 390 ]

[0416] The modulators of the present invention, such as Sequence IDs 1, 2, 5-13, are used herein in relation to the present invention. The term "derivative" refers to a derivative whose primary structure is the C-terminal cytoplasmic tail of RAGE or its Obtained from or derived from fragments, but with amino acid addition, substitution, cleavage, chemical and / or biochemical modifications (acetylation, carboxylation, phosphorylation, glycosylation, ubiquitination) Labeling with radioactive nucleotides or halogens, abnormal or artificial amino acids (side chain methylation, side chain methylation), radioactive nucleotides or halogens, abnormal or artificial amino acids. Acids (D-amino acids, N-methylated amino acids, tetrasubstituted amino acids, β-peptides, pyroglutamic acid; 2-aminoadipic acid; 3-aminoadipic acid; β-alanine; β-aminopropionic acid ;2-aminobutyric acid;4-aminobutyric acid;piperidine acid;6-aminocaproic acid;2-amino Heptanoic acid; 2-aminoisobutyric acid; 3-aminoisobutyric acid; 2-aminopimelic acid; 2,4 -Diaminobutyric acid; desmosine; 2,2''-diaminopimeric acid; 2,3-diaminopro Pionic acid; N-ethylglycine; N-ethyl asparagine; hydroxylysine; Alo-H Droxylysine; 3-hydroxyproline; 4-hydroxyproline; isodesmosine; Allo-isoleucine; N-methylglycine; sarcosine; N-methylisoleucine; N- Methylvaline; norvaline; norleucine; ornithine; statins, etc.), retro-reverse configuration Rows, cyclic peptides, peptoids or non-peptide drugs, non-peptide labels, non-peptide carriers Alternatively, it refers to a modulator characterized by linking to a non-peptide resin.

[0417] The inventors have developed a peptide (SEQ ID NO: 14) containing residues 343-361 of wild-type RAGE. However, both RAGE ligand-independent RAGE activation and RAGE ligand-dependent activation We further discovered that it is an inhibitory peptide that inhibits the process.

[0418] Substitution is an amino acid change in which an amino acid is replaced by a different native or non-conventional amino acid residue. To include. Such substitutions can be classified as "conservative," and in this case, polyp The amino acid residues contained in butyl are similar in terms of polarity, side-chain functionality, or size. It is substituted with another natural amino acid with the same properties, for example, Ser⇔Thr⇔Pro⇔Hyp⇔Gl y⇔Ala, Val⇔Ile⇔Leu, His⇔Lys⇔Arg, Asn⇔Gln⇔As p⇔Glu or Phe⇔Trp⇔Tyr. Some unconventional amino acids are also naturally occurring. It should be understood that it can be a suitable substitute for existing amino acids. For example, ornithine, Homoarginine and dimethyllysine are related to His, Arg, and Lys.

[0419] The substitutions included in this invention may be "non-conservative" and involve amino acids present in polypeptides. The residues are amino acids with different properties, such as naturally occurring amino acids from different groups. They are either replaced (for example, by substituting charged or hydrophobic amino acids with alanine) or instead In this process, naturally occurring amino acids are replaced with unconventional amino acids.

[0420] Amino acid substitutions are typically single-residue substitutions, but can also be clustered or dispersed. The substitution may involve multiple residues. Preferably, the amino acid substitution is conservative.

[0421] Additions include the addition of one or more native or unconventional amino acid residues. Deletions include the addition of one or more This includes the deletion of the amino acid residue above.

[0422] As described above, the present invention comprises a peptide in which one or more amino acids have undergone side-chain modification. Examples of side-chain modifications intended by the invention include reactions with aldehydes and subsequent NaBH Reductive alkylation by reduction at 4; Amidineization by methyl acetimidate; Anhydrous vinegar Acid acylation; Carbamoylation of amino groups by cyanates; 2,4,6-trinitrate Trinitrobenzylation of amino groups by benzobenzenesulfonic acid (TNBS); anhydrous succinate Acylation of amino groups with acids and tetrahydrophthalic anhydride; and pyridoxal-5- Pyridoxylation of lysine by phosphate and subsequent reduction by NaBH4, etc. It includes modifications of the base.

[0423] The guanidine group of the arginine residue contains 2,3-butanedione, phenylglyoxal, and It can be modified by the formation of heterocyclic condensation products with reagents such as biglyoxal.

[0424] The carboxyl group is involved in carbodiimide activation via O-acyl isourea formation and It can be modified by subsequent derivatization, for example, derivatization to the corresponding amide. The carboxymethylation of the syl group with iodoacetic acid or iodoacetamide; cyste of performic acid Oxidation to ionic acid; formation of mixed disulfides with other thiol compounds; maleimide, anhydride Reaction with leic acid or other substituted maleimides; 4-chloromercuric benzoic acid, 4-chloromercuric phosphate Phenylsulfonic acid, phenylmercury chloride, 2-chloromercury-4-nitrophenol and other Formation of mercury derivatives using mercury agents; carbamoylation with cyanates at alkaline pH. It can be modified by methods such as chemical modification. In a preferred embodiment of the present invention, any of the cysteine ​​residues The modifications must not affect the peptide's ability to form the necessary disulfide bonds. The sulfhydryl group of stein is replaced with a selenium equivalent, resulting in a peptide with one or more disulfide groups. It is also possible to form a diselenium bond instead of a filtrate bond.

[0425] Tryptophan residues can be oxidized, for example, by N-bromosuccinimide or 2-hydro The indole ring by xy-5-nitrobenzyl bromide or sulfenyl halide It can be modified by alkylation. On the other hand, the tyrosine residue can be modified by tetranitromethane. Nitration can alter the 3-nitrotyrosine derivative.

[0426] Modification of the imidazole ring of a histidine residue is performed by alkylation or dihydroxylation with an iodoacetic acid derivative. This can be achieved by N-carboethoxylation with ethyl pyrocarbonate. Proline The residue can be modified, for example, by hydroxylation at position 4.

[0427] The following table lists some amino acids with modified side chains and other unnatural amino acids. This will be shown.

[0428] [Table 29]

[0429] These types of modifications, when administered to an individual or used as a diagnostic reagent, This may be important for stabilizing the ptide.

[0430] The conserved amino acid substitutions used herein refer to substitutions between members of the group that affect the biological properties of the molecule. To preserve the activity (see, for example, Grantham, R., 1974), It may contain amino acid residues within the group that have sufficiently similar physicochemical properties. In particular, it may contain conservative amino acids. amino acid substitution involves substituting amino acids of the same class (e.g., basic amino acids, acidic amino acids). Acids, polar amino acids, amino acids with aliphatic side chains, amino acids with positively or negatively charged side chains No acids, amino acids having aromatic groups in their side chains, side chains that can enter hydrogen bridges, for example, hydroxyl groups The substitution is preferably derived from an amino acid having a side chain with a roxyl functional group. Conservative substitutions, in this case, for example, involve basic amino acid residues (Lys, Arg, His). Substitution with other basic amino acid residues (Lys, Arg, His), aliphatic amino acid residues By substituting the base (Gly, Ala, Val, Leu, lie) with another aliphatic amino acid residue... This involves substituting aromatic amino acid residues (Phe, Tyr, Trp) with other aromatic amino acid residues. This involves substituting threonine with serine or leucine with isoleucine. Conservative amino acid exchanges will be known to those skilled in the art. The isomer form is preferably, It should be maintained, for example, K preferably substitutes R or H, and k preferably This substitutes r and h.

[0431] When considering amino acid substitutions, the preferred substitutions of the present invention are those of Grantham, R. ( It is stated in 1974 that it has a D of less than 100, and the details are as follows: More integrated. The most preferred alternative is one described as having a D of less than 50. That is the case.

[0432] The peptide modulator of the present invention corresponds to SEQ ID NOs: 1, 2, 5, 6, 7, 8, 9, 10, 1 Retroinverso isomers or modified or substituted variants of 1, 12, or 13 or Includes peptides formed by addition or deletion (Li et al., 2010) .

[0433] <Method for treating, preventing or managing RAGE-related disorders> In another related aspect, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention. In another related aspect, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention. In another related aspect, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention. In another related aspect, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention.

[0434] In another aspect, the present invention relates to the use of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR for the manufacture of a medicament for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment. In another aspect, the present invention relates to the use of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR for the manufacture of a medicament for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment. In another aspect, the present invention relates to the use of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR for the manufacture of a medicament for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment.

[0435] In another aspect, the present invention relates to the use of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment. In another aspect, the present invention relates to the use of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment. In another aspect, the present invention relates to the use of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment.

[0436] In a preferred form of the present invention, the particular co-existing GPCR is an angiotensin receptor. In a preferred form of the present invention, the particular co-existing GPCR is AT1R.

[0437] In a preferred form of the present invention, the particular co-existing GPCR is a particular chemokine receptor. In a preferred form of the present invention, the particular co-existing GPCR is CCR2.

[0438] Furthermore, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention and a particular Furthermore, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention and a particular Furthermore, the present invention provides a method for treating, preventing or managing RAGE-related disorders in a patient that requires such treatment, the method comprising administering an effective amount of a modulator of RAGE ligand-independent RAGE activation by a particular activated co-existing GPCR of the present invention and a particular Modulators of specific coexisting GPCRs and / or specific coexisting GPCR signaling pathways This includes administration in combination with a juter.

[0439] In a preferred embodiment of the present invention, a specific coexisting GPCR is an angiotensin receptor. In a preferred embodiment of the present invention, the specific coexisting GPCR is AT1R.

[0440] In a preferred embodiment of the present invention, a specific coexisting GPCR is a specific chemokine receptor. In a preferred embodiment of the present invention, the specific coexisting GPCR is CCR2.

[0441] The method involves using an effective amount of the RAGE ligand activated by a specific coexisting GPCR of the present invention. RAGE activation-independent modulators and modulators of specific coexisting GPCRs and / or administration in combination with modulators of specific coexisting GPCR signaling pathways This may include, where, a modulator of a specific coexisting GPCR and / or a specific coexisting GPCR. GRNAL transmission pathway modulators are used to address disruptions related to specific coexisting GPCRs. It is administered at a lower dose than the usual dose.

[0442] The method involves using an effective amount of the RAGE ligand activated by a specific coexisting GPCR of the present invention. RAGE activation-independent modulators and modulators of specific coexisting GPCRs and / or administration in combination with modulators of specific coexisting GPCR signaling pathways This may include, where, a modulator of a specific coexisting GPCR and / or a specific coexisting GPCR. Modulators of the Gunal signaling pathway are typically administered to treat disorders related to RAGE. It is administered at a lower dose than that.

[0443] In a particularly preferred embodiment of the present invention, the method involves an effective amount of the activated angiotensin of the present invention. Receptor-mediated modulators of RAGE ligand-independent RAGE activation and AT1R Modulators and / or modulators of the AT1R signaling pathway This includes administration of the AT1R modulator and / or AT1R signaling pathway. The modulator is administered at a lower dose than is normally given for the treatment of AT1R-related disorders. It will be administered.

[0444] In another particularly preferred embodiment of the present invention, the method involves an effective amount of the activated specific of the present invention. A modulator of chemokine receptor-mediated RAGE ligand-independent RAGE activation and , with CCR2 modulators and / or modulators of the CCR2 signaling pathway This includes combination administration, where CCR2 modulator and / or CCR2 signaler Modulators of the CCR2 transmission pathway are administered more than usual for the treatment of CCR2-related disorders. It is administered in low doses.

[0445] Furthermore, the present invention relates to the treatment, prevention, or management of RAGE-related disorders, which require such treatment. The present invention provides a method for use in patients, the method comprising an effective amount of the activated specific of the present invention. A modulator of RAGE ligand-independent RAGE activation by coexisting GPCRs, and R Modulators for the RAGE ligand-dependent activation of AGEs, and / or constitutively active RAs. GE modulators and / or RAGE signaling pathway modulators in combination This includes combined administration.

[0446] In a particularly preferred embodiment of the present invention, the method involves an effective amount of the activated specific coexistence of the present invention. A modulator of RAGE ligand-independent RAGE activation by GPCR, and RAG A modulator of RAGE ligand-dependent activation of E, and / or constitutively activated RAGE Modulators of and / or combinations with modulators of the RAGE signaling pathway This includes the administration of a modulator of RAGE ligand-dependent activation, and / or constitutively active RAGE modulators and / or RAGE signaling pathways Pathway modulators are administered at lower doses than those typically given for the treatment of RAGE-related disorders. It is administered as follows.

[0447] Furthermore, the present invention relates to the treatment, prevention, or management of RAGE-related disorders, which require such treatment. The present invention provides a method for use in patients, the method comprising an effective amount of the activated specific of the present invention. A modulator of RAGE ligand-independent RAGE activation by coexisting GPCRs, and Modulators of specific coexisting GPCRs and / or specific coexisting GPCR signaling pathways This includes administration in combination with a juter.

[0448] For example, the present invention relates to the treatment, prevention, or management of RAGE-related disorders, which require such treatment. The present invention provides a method for use in patients, and the method involves using an effective amount of the activated angiotenoid of the present invention. A modulator of RAGE ligand-independent RAGE activation by syn receptors, and RA A modulator of GE's RAGE ligand-dependent activation, and / or constitutively active RAG Modulators for E, and / or modulators for the RAGE signaling pathway, and AT Combinations of 1R modulators and / or modulators of the AT1R signaling pathway This includes administering the drug.

[0449] For example, the present invention relates to the treatment, prevention, or management of RAGE-related disorders, which require such treatment. The present invention provides a method for use in patients, the method comprising an effective amount of the activated specific of the present invention. A modulator of chemokine receptor-mediated RAGE ligand-independent RAGE activation and , modulators of RAGE ligand-dependent activation, and / or constitutive activators RAGE modulators, and / or modulators of the RAGE signaling pathway, with CCR2 modulators and / or modulators of the CCR2 signaling pathway This includes combination therapy.

[0450] In a particularly preferred embodiment of the present invention, the method involves an effective amount of the activated specific coexistence of the present invention. A modulator of RAGE ligand-independent RAGE activation by GPCR, and specific Modulators of coexisting GPCRs and / or the signaling pathways of specific coexisting GPCRs A modulator and a modulator of RAGE ligand-dependent activation, and / or It is a modulator of constitutively active RAGE and / or a modulator of the RAGE signaling pathway. This includes administration in combination with a regulator, where RAGE ligand-dependent activity of RAGE Modulators for transformation, and / or modulators for constitutively active RAGE, and / or Modulators of the RAGE signaling pathway are typically used to treat RAGE-related disorders. Administered at a lower dose than that given, and / or a modulator of a specific coexisting GPCR and And / or modulators of the signaling pathways of specific coexisting GPCRs are related to GPCRs. It is administered at a lower dose than that normally used to treat the disorder.

[0451] In a particularly preferred embodiment of the present invention, the method involves an effective amount of the activated angiotensin of the present invention. Receptor-mediated modulators of RAGE ligand-independent RAGE activation and AT1R modulators and / or modulators of the AT1R signaling pathway and RAGE A modulator of RAGE ligand-dependent activation, and / or constitutively activated RAGE. Modulators, and / or combinations with modulators of the RAGE signaling pathway. This includes the administration of a modulator of RAGE ligand-dependent activation, and and / or constitutively active RAGE modulators and / or RAGE signaling pathways The modulator is administered at a lower dose than is typically given for the treatment of RAGE-related disorders. Administered and / or AT1R modulators and / or AT1R signaling pathways Modulators are administered at lower doses than those typically used to treat AT1R-related disorders. To be given.

[0452] In a particularly preferred embodiment of the present invention, the method involves using an effective amount of the activated specific chemo A modulator of RAGE ligand-independent RAGE activation by the kine receptor, and C CR2 modulators and / or modulators of the CCR2 signaling pathway and R Modulators for the RAGE ligand-dependent activation of AGEs, and / or constitutively active RAs. GE modulators and / or RAGE signaling pathway modulators in combination This includes combined administration, where the modulator of RAGE ligand-dependent activation of RAGE. - and / or constitutively activated RAGE modulators and / or RAGE signal propagation The modulator of the delivery route is administered at a lower dose than is typically given for the treatment of RAGE-related disorders. Administered in doses and / or acts as a CCR2 modulator and / or CCR2 signaling molecule. The pathway modulator is administered at a lower dose than is typically given for the treatment of CCR2-related disorders. It is administered by dose.

[0453] RAGE-related disorders are defined as disorders that depend on the expression of RAGE. Certain co-occurring disorders, such as AT1R-related disorders or CCR2-related disorders, which are also dependent on GE expression. This does not rule out PCR-related problems. In fact, if the problem is RAGE-related... This includes cases where the condition is related to specific coexisting GPCRs, including AT1R-related or CCR2-related ones. That is possible.

[0454] Disorders associated with specific coexisting GPCRs are considered disorders dependent on the expression of those specific coexisting GPCRs. This is defined as RAGE-related disorders that also depend on the expression of certain coexisting GPCRs. This does not exclude anything. In fact, the failure may be RAGE-related, or AT1R-related or C This could be related to specific coexisting GPCRs, including CR2-related ones.

[0455] In one embodiment of the present invention, RAGE-related disorders include: cardiovascular disorders; gastrointestinal diseases; cancer; and neurological disorders. Disorders, respiratory disorders, connective tissue disorders, kidney disorders, reproductive disorders, skin disorders, eye disorders, endocrine disorders It is a disorder that is selected from among the harmful.

[0456] In one embodiment of the present invention, RAGE-related disorders include: atherosclerosis, ischemic heart disease. Diseases, myocarditis, endocarditis, cardiomyopathy, acute rheumatic fever, chronic rheumatic heart disease, cerebrovascular disease / Cardiovascular disorders selected from stroke, heart failure, vascular calcification, peripheral vascular disease, and lymphangitis. ru.

[0457] In one embodiment of the present invention, RAGE-related disorders include: periodontitis, esophagitis, gastritis, and gastroduodenal ulcers. Surgery, Crohn's disease, ulcerative colitis, ischemic colitis, enteritis and enterocolitis, peritonitis, alcohol Toxic liver disease, hepatitis, toxic liver disease, biliary cirrhosis, hepatic fibrosis / cirrhosis, non-alcoholic lipids Fatty liver / non-alcoholic steatohepatitis (NAFLD / NASH), liver trauma and liver injury, trauma or This is a digestive disorder selected during recovery from surgery.

[0458] In one embodiment of the present invention, RAGE-related disorders include: malignant neoplasms of the lips, oral cavity and pharynx, digestive disorders. Malignant neoplasms of organs, malignant neoplasms of respiratory and intrathoracic organs, malignant neoplasms of bone and articular cartilage, black Pigmentomas and other malignant neoplasms of the skin, malignant neoplasms of the mesothelium and soft tissue, malignant neoplasms of the breast, female Malignant neoplasms of the reproductive organs, malignant neoplasms of the male reproductive organs, malignant neoplasms of the urinary tract, eyes, brain and central nervous system Malignant neoplasms of other parts of the system, malignant neoplasms of the thyroid and other endocrine glands, lymphatic system, hematopoietic system and malignant neoplasms of related tissues, malignant neoplasms of unclear, secondary and / or unspecified sites. It is a type of cancer that is selected by the organism.

[0459] In one embodiment of the present invention, RAGE-related disorders are neurological disorders and group: inflammation of the central nervous system. Symptomatic diseases, systemic atrophy mainly affecting the central nervous system, extrapyramidal and motor disorders, parkin Son's disease, demyelinating diseases of the central nervous system, Alzheimer's disease, focal brain atrophy, Lewy body dementia, Epilepsy, migraines, neuropathic pain, diabetic neuropathy, polyneuropathy, and glioma development. and progression, spinal cord injury, ischemic brain injury / stroke, traumatic brain injury and brain injury, recovery from trauma or surgery Selected from the list.

[0460] In one embodiment of the present invention, RAGE-related disorders are mental disorders and belong to the group: dementia, Alzheimer's disease. Heimer's disease, vascular dementia, addiction, schizophrenia, major emotional disorders, depression, mania, bipolar disorder The choice is made from a disorder or an anxiety disorder.

[0461] In one embodiment of the present invention, RAGE-related disorders are respiratory (lung) disorders and belong to the group: acute upper Respiratory tract infections, rhinitis, nasopharyngitis, sinusitis, laryngitis, influenza and pneumonia, acute bronchitis Inflammation, acute bronchiolitis, asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, external Chronic lung disease caused by the following factors: acute respiratory distress syndrome (ARDS), pulmonary eosinophilia and pleurisy, lung The selection is made from trauma and lung injury, or recovery from trauma or surgery.

[0462] In one embodiment of the present invention, RAGE-related disorders are connective tissue disorders, and group: osteoarthritis Inflammation, infectious arthritis, rheumatoid arthritis, psoriatic and enteric arthropathy, juvenile arthritis, gout and Other crystalline arthropathy, diabetic arthropathy, polyarteritis nodosa, Churg-Strauss syndrome, mucosal arthropathy Cutaneous lymph node syndrome [Kawasaki], hypersensitivity vasculitis, Goodpasture syndrome, thrombotic microangiopathy Wegener's granulomatosis, aortic arch syndrome [Takayasu], giant cell arteritis, polymyalgia rheumatica Pain, microscopic polyangiitis, hypocomplementary vasculitis, systemic lupus erythematosus, cutaneous polymyositis Polymyositis, systemic sclerosis, CR(E)ST syndrome, dryness syndrome [Sjögren's], mixed Selected from connective tissue disease, Behçet's disease, traumatic muscle injury, sprain, muscle contusion, and fracture. .

[0463] In one embodiment of the present invention, RAGE-related disorders are defined as renal disorders and include: glomerulonephritis, nephritis. From diabetic nephropathy, interstitial nephritis, obstructive and reflux nephropathy, acute renal failure and chronic kidney disease Selected.

[0464] In one embodiment of the present invention, RAGE-related disorders are reproductive disorders and include: prostatitis, pre- Prostatic hyperplasia, prostatic dysplasia, salpingitis, oophoritis, pelvic inflammatory disease (PID), polycystic ovary syndrome The diagnosis is selected from syndrome, cervicitis, cervical dysplasia, vaginitis, and vulvitis.

[0465] In one embodiment of the present invention, RAGE-related disorders include: dermatitis, eczema, pemphigus / bullous pemphigoid, and dry skin. Tinea, pityriasis rosea, lichen planus, urticaria, erythema multiforme, erythema nodosum, sunburn, keratosis, photoaging It is a skin disorder selected from ulcerative cutaneous ulcers, superficial skin injuries, and open wounds.

[0466] In one embodiment of the present invention, RAGE-related disorders include: keratitis, conjunctivitis, retinitis, glaucoma, severe Optic neuritis, episcleritis, chorioretinal inflammation, diabetic retinopathy, macular edema, retinopathy of prematurity, and optic neuritis , eye disorders selected from eye trauma and eye injury, recovery from trauma or surgery.

[0467] In one embodiment of the present invention, RAGE-related disorders include: diabetes mellitus, insulin resistance, and impaired glucose tolerance. It is an endocrine disorder selected from harm and thyroiditis.

[0468] In one embodiment of the present invention, AT1R is inhibited or the AT1R signaling pathway is inhibited. The inhibitors include: eprosartan (trade name Teveten®, Abbott) Laboratories USA), losartan (trade name Cozaar® registered trademark), Merck&Co), Valsartan (trade name: Diovan(R)), Novarti s), telmisartan (trade name Micardis®, Boehringer Ingelheim), Irbesartan (trade name Avapro (registered trademark), Sanof iAventis), Olmesartan (brand name Benicar (registered trademark), Daiic hi Sankyo Inc., Azilsartan (product names Edarbi, Takeda) Candesartan (trade name Atacand®, AstraZeneca), Z D-7115, Sararacin ((Sar1-Ala8)Ang II), Sarsuran ((S Selected from ar1-Thr8)Ang II) and DuP753. This list includes, These also include prodrugs of these inhibitors, such as candesartan (candesartan cilate). Xetyl), azilsartan (azilsartan medoxomil) and olmesartan (ol It contains mesartan medoxomil, and the forms in which they are administered and their active metabolites (losalta). It may be the active metabolite of agonist EXP-3174. Partial agonists are agonists. Because even if it shows a zyme, it does not produce the maximum effect, partial agonists suppress endogenous Ang II It can act to inhibit, and therefore can act as a therapeutic inhibitor. Please take note.

[0469] In one embodiment of the present invention, a specific chemokine receptor is inhibited, or a specific chemokine receptor is inhibited. Inhibitors that inhibit the Gunal signaling pathway include: propagermanium(3-[(2-carboxy Ethyl-oxogelmyl)oxy-oxogelmyl] Also known as propanoic acid, Xygermanium, Ge-132, bis(2-carboxyethylgermanium)sesquiol Hoxide (CEGS), 2-carboxyethyl germasesquioxane, SK-818, Organic Germanium, germanium sesquioxide, 3,3'-(1,3-dioxo-1,3- Digermanoxanediyl)bispropionic acid, 3-oxygelmylpropionic acid polymer , poly-trans-(2-carboxyethyl) germasesquioxane, proxy german Um, repagermanium and celocion; CCR2), BMS CCR2 22 (CCR 2) Resveratrol (CCR2), RS504393 (CCR2), RS10289 5 (CCR2), MLN-1202 (Millennium Pharmaceutic als;CCR2), INCB8696(Incyte Pharmaceutical s;CCR2), MK-0812(Merck;CCR2), CCX140(Chemo Centryx;CCR2), PF-4136309(Pfizer;CCR2), BM S-741672 (Bristol-Myers Squibb; CCR2); Reperta Kixine (CXCR2), TAK-779 (CCR5), TAK-220 (CCR5), T AK-652(CCR5), AK692(CCR5), CMPD167(CCR5), B X-471(CCR1), AMD3100(CXCR4), AMD11070(CXCR 4), FC131 (CXCR4), MLN3897 (CCR1), CP-481715 ( CCR1), GW-873140 (CCR5), SB 225002 (CXCR2) and Selected from SB 265610(CXCR2).

[0470] In one embodiment of the present invention, CCR2 is inhibited or the CCR2 signaling pathway is inhibited. The inhibitors include: propagermanium (3-[(2-carboxyethyl-oxogermyl) )Oxy-oxogelmyl] Also known as propanoic acid, proxigermanium, Ge -132, Bis(2-carboxyethylgermanium)sesquioxide (CEGS), 2 -Carboxyethyl germasesquioxane, SK-818, Organic germanium, Germanium trioxide Lumanium, 3,3'-(1,3-dioxo-1,3-digermanoxanediyl)bisp Ropionic acid, 3-oxygelmylpropionic acid polymer, poly-trans-(2-carb Xyethyl germasexine, proxigermanium, repagermanium and cello Shion), BMS CCR2 22 (CCR2), Resveratrol (CCR2), RS 504393, RS102895, MLN-1202(Millennium Phar maceuticals), INCB8696(Incyte Pharmaceuti cals), MK-0812 (Merck), CCX140 (ChemoCentryx) ), PF-4136309 (Pfizer), BMS-741672 (Bristol My Selected from (Yardsquib).

[0471] In one embodiment of the present invention, an inhibitor of RAGE ligand-dependent activation of RAGE, and / or Inhibitors of constitutively active RAGE and / or inhibitors of the RAGE signaling pathway belong to the group: Azerylagon (TTP488 / PF-04494700) (RA targeting the V domain) Oral small molecule inhibitors of GE-ligand interaction); TTP4000 (US 79814) Ligand-binding external of RAGE linked to the human Ig Fc domain as described in Specification No. 23 A soluble fusion protein inhibitor of RAGE using a domain; International Publication No. 20071 Specific to RAGE and its RAGE-binding fragment as described in pamphlet No. 09747 Antibodies that bind to Aβ / RAGE; FPS-ZM127 (high affinity, blocks Aβ / RAGE interaction) Grade amide; RAGE rig, as described in U.S. Patent Application Publication No. 20100249038. Peptides that antagonize signaling pathways; International Publication No. 2012109569 Pamphlet Lysophosphatidic acid (LPA) antagonist as described in the list; Han et al. 2-aminopyrimidine as described in 2012; pyrimidine as described in Han et al (2014) Razole-5-carboxamide; 4,6-bis as described by Han et al (2015) Phenyl-2-(3-alkoxyanilino)pyrimidine; Manigrasso et al. Small molecule inhibition of ligand-stimulated RAGE-DIAPH1 signaling as described in al (2016). Harmful agent; RAGE cytoplasm as described in U.S. Patent Application Publication No. 20090220484 Essentially consisting of all or part of the lateral tail, or bound to the cytoplasmic lateral tail of RAGE. It is selected from polypeptides that are essentially derived from a portion of Diaphanous-1.

[0472] In certain embodiments, the modulator is a screening device as described extensively herein. Using a method or a method for identifying modulators, an angiotensin such as AT1R Activated specific coexisting G receptors, such as the syn receptor or certain chemokine receptors like CCR2. Identified as a modulator of RAGE ligand-independent RAGE activation by PCR. It is administered to the target based on the following criteria.

[0473] AT1R-related disorders are defined as disorders that depend on the expression of AT1R. This does not exclude RAGE-related disorders, which are also dependent on the expression of 1R. In fact, the disorders are, It could be related to both RAGE and AT1R.

[0474] Specific chemokine receptor-related disorders are disorders that depend on the expression of specific chemokine receptors. This is defined as RAGE-related, which also depends on the expression of specific chemokine receptors. This does not rule out the possibility of impairment. In fact, the impairment is related to RAGE and certain chemokine receptors. It could be both related and unrelated.

[0475] CCR2-related disorders are defined as disorders that depend on the expression of CCR2. This does not exclude RAGE-related disorders, which are also dependent on R2 expression. In fact, the disorders are, It could be related to both RAGE and CCR2.

[0476] For combination medications, the following dosages are "usually" administered.

[0477] [Table 30]

[0478] <Screening methods for candidate drugs> In one embodiment, the present invention involves a candidate drug being subjected to RAGE induction by an active coexisting GPCR. The method includes a method for screening the ability of a candidate drug to modulate activity, and the method includes the existence of The step involves contacting the RAGE polypeptide with the GPCR polypeptide under the current conditions, and here, GPCR polypeptides are constitutively active and / or agonists of their GPCRs. Activated by the addition of a partial agonist or allosteric modulator; candidate By detecting the effect of the drug on modulating RAGE activation, and / or by detecting the potential effect. By detecting RAGE-dependent signaling regulated by the presence of supplemental drugs, The supplemental drug enables RAGE ligand-independent activation by activated coexisting GPCRs. The process includes the step of detecting whether it is a modulator of

[0479] In one embodiment, the present invention relates to a candidate drug that targets an angiotensin receptor such as AT1R or CC RAG is mediated by specific coexisting GPCRs, such as certain chemokine receptors like R2. E-ligand-independent RAGE activation (RAGE ligand-independent activation of RAGE) It regulates (i.e., activates, inhibits, or allostericly modulates) sexualization. This includes methods for screening the ability of. These methods generally include, a. Contacting the RAGE polypeptide with the GPCR polypeptide in the presence of the candidate drug. And here, the GPCR polypeptide is constitutively active and / or its GPCR Activation by the addition of an agonist, partial agonist, or allosteric modulator. To be transformed; and b. By detecting the effect of the candidate drug on modulating RAGE activation, and To detect RAGE-dependent signaling that is regulated by the presence of one or a candidate drug. Therefore, candidate drugs can be used to treat RAGE ligand-independent RA mediated by activated coexisting GPCRs. Detecting whether it is a modulator of GE activation It includes, consists of, or is essentially derived from.

[0480] In some embodiments, the screening method is performed in the presence or absence of RAGE. The candidate drugs are identified as being related to angiotensin receptors such as AT1R or specific receptors such as CCR2. Modulators (activators, inhibitors, etc.) of specific coexisting GPCRs, such as chemokine receptors. Angiotensins such as rosteric modulators or the AT1R signaling pathway Specific chemocal receptor signaling pathways such as the CCR2 signaling pathway, or other specific chemocal receptor signaling pathways such as the CCR2 signaling pathway. Modulation of specific coexisting GPCR signaling pathways, such as the ion receptor signaling pathway. Detect whether it is a ter (activator, inhibitor, allosteric modulator, etc.) This further includes the following: In some embodiments, if a RAGE polypeptide is present, Candidate drugs that provide greater signal modulation compared to when they are not present are coexisting Rather than RAGE-independent signaling resulting from GPCR activation, activated coexisting G PCR is selective for the regulation of RAGE activation in a RAGE ligand-independent manner.

[0481] In one embodiment, the present invention relates to a peptide identified as a modulator by the above method. Includes. In one embodiment, the present invention relates to compounds identified as modulators by the method described above. Includes.

[0482] In some embodiments, the screening method involves an angiotensin receptor such as AT1R. The presence of specific coexisting GPCRs, such as certain chemokine receptors like CCR2, or other factors related to the body's condition. Under or in the absence of a candidate drug, the RAGE or RAGE signaling pathway module In addition to activators (such as activators, inhibitors, allosteric modulators, or functional substitutes) This further includes detecting whether or not they are present. In some embodiments, GPCRs When CHIDS are present, the RAGE-dependent signal is larger compared to when they are not present. Candidate drugs that induce significant regulation are RAGE ligand-independent via activated coexisting GPCRs. It is selective in regulating the activation of RAGE in living organisms.

[0483] In some embodiments, the screening method involves a candidate drug being RAGE polypeptide Alternatively, the RAGE signaling pathway and angiotensin receptors such as AT1R or CC Specific coexisting GPCRs or AT1R signaling pathways, such as those involving specific chemokine receptors like R2. Angiotensin receptor signaling pathways such as the CCR2 signaling pathway, or other such pathways. Sigma of specific coexisting GPCRs, such as specific chemokine receptor signaling pathways. Modulators of the cellular signaling pathway (activators, inhibitors, allosteric modulators or This further includes detecting whether it is a functional substitute, etc.

[0484] In some embodiments, the screening method binds to the extracellular domain of RAGE. Therefore, RAGE ligands inhibit RAGE activation in a RAGE ligand-dependent manner. This further includes using inhibitors of the drug.

[0485] In some embodiments, the screening method is a RAGE polypeptide. Therefore, it was not possible to bind the RAGE ligand to its external domain, and therefore Mutations and / or cuts are made so that RAGE cannot be activated in a ligand-dependent manner. This further includes the use of RAGE polypeptides that have been discontinued.

[0486] In some embodiments, the modulation modulates the binding of RAGE ligands to RAGE. Exposure of cells to the ter allows for the binding of RAGE ligands to the extracellular domain of RAGE. The combination will be compromised.

[0487] In some embodiments, it is unable to bind the RAGE ligand, and Therefore, mutations are introduced to prevent activation in a RAGE ligand-dependent manner. The use of cleaved and / or cleaved RAGE polypeptides allows RA to bind to RAGE ligands. This occurs before, after, or concurrently with screening involving GE polypeptides.

[0488] Appropriately, angiotensin receptors such as AT1R or specific chemokinetics such as CCR2 RAGE ligand-independent RA by activated specific coexisting GPCRs, such as RA receptors. It modulates GE activation and appropriately controls angiotensin receptors such as AT1R or CCR2 Certain coexisting GPCRs and / or AT1R signaling pathways, such as specific chemokine receptors. Angiotensin receptor signaling pathways such as the CCR2 signaling pathway, or other similar pathways. The signaling pathways of specific chemokine receptors, such as the signaling pathways of specific coexisting GPCRs It modulates the Gnul signaling pathway and / or inhibits the RAGE ligand-dependent activation of RAGE. and / or candidate candidates that inhibit constitutively active RAGE and / or the RAGE signaling pathway. The drug or a derivative of the candidate drug is particularly useful for the treatment, prevention, or management of RAGE-related disorders. .

[0489] In a specific embodiment of the screening method of the present invention, the candidate drug is RAGE polypeptide It modulates the RAGE-dependent signal detected when it comes into contact with GPCR polypeptides. If so, the method is to use RAGE-dependent signals when GPCR polypeptides are present. Candidate drugs that provide significant regulation include those activated by coexisting GPCRs as RAGE ligands. To be selective in regulating RAGE activation independently, GPCR polypeptides Whether and / or to what extent a candidate drug modulates RAGE-dependent signaling in the absence of the drug. This further includes making a decision.

[0490] In a specific embodiment of the screening method of the present invention, the candidate drug is RAGE polypeptide When modulating the signal detected when the drug comes into contact with a GPCR polypeptide, the method This determines whether the signal is generated in the absence of the RAGE polypeptide and / or to what extent. Determine the degree, and if the signal is generated in the absence of RAGE polypeptide, RAG Candidate drugs that provide greater signal modulation when E polypeptides are present coexisting Rather than RAGE-independent signaling resulting from GPCR activation, activated coexisting G PCR is selective in its ability to regulate RAGE activation in a RAGE ligand-independent manner. Furthermore, whether candidate drugs modulate signaling in the absence of RAGE polypeptides and / or further including determining the degree thereof.

[0491] In a particular embodiment, the screening method is proximity screening. Using a ping assay, RAGE polypeptides, such as AT1R, are subjected to angiotensin receptors. The proximity to specific coexisting GPCRs, such as the body or specific chemokine receptors like CCR2. Evaluate. In this type of exemplary example, the RAGE polypeptide is the first reporter component. Coupled (for example, conjugated or otherwise connected) to AT1R and other A Certain coexisting GPs, such as ngiotensin receptors or specific chemokine receptors like CCR2. CR is coupled to the second reporter component (e.g., by conjugation or other means). (Linked together). The proximity of the first and second reporter components allows detection by the detector. A gunal is generated. The first and second reporter components have a clear effect on the function of the present invention. This means that the first reporter component can be exchanged for the second reporter component without giving anything to the first. They form a complementary pair in terms of taste. The first and second reporter components are either the same or different. obtain.

[0492] In one embodiment, the proximity screening assay uses a Receptor Heterom er Investigation Technology or Receptor-HI Also known as T (Jaeger et al., 2014), International Publication No. 20080 Brochure No. 55313 (Dimerix Bioscience Pty Ltd;) Also, U.S. Patent No. 8,283,127, U.S. Patent No. 8,568,997, European Patent Patent No. 2080012, Canadian Patent No. 2669088, Chinese Patent No. 1016 This is as described in Specification No. 57715. In this method, RAGE is the first reporter It is coupled to components such as angiotensin receptors like AT1R or specific receptors like CCR2. Certain coexisting GPCRs, such as specific chemokine receptors, are relevant to proximity screening assays. The GPCR interacting group is not labeled, and is linked to a complementary second reporter component, forming a complex. Its interaction with the body is selective ligand for unlabeled GPCRs or, in particular, heteromer complexes. It is regulated when bound. Preferred examples of GPCR interacting groups are arrestin and G proteins. It is a receptor and ligand. Alternatively, it is an angiotensin receptor such as AT1R or CCR. Certain coexisting GPCRs, such as specific chemokine receptors like 2, can be linked to the first reporter component. Coupled, RAGE is unlabeled with respect to proximity screening assays, RA The GE interacting group is linked to a complementary second reporter component, and its interaction with the complex. This modulates when a ligand selectively binds to unlabeled RAGE or, in particular, to heteromer complexes. A preferred example of a RAGE interacting group is IQGAP-1, Diaphanous 1. Dock7, MyD88, TIRAP, IRAK4, ERK1 / 2, and PKCζ, etc. It is a protein that interacts with the cytoplasmic tail of RAGE (Jules et al. .,2013;Ramasamy et al.,2016).

[0493] The reporter component incorporates an enzyme, a luminescent or bioluminescent molecule, a fluorescent molecule, and an enzyme cleavage site. The linker then links RAGE to specific coexisting GPCRs or interacting groups. It may include photomorphisms or other molecules. In short, detectable as a result of their spatial proximity. Organic or inorganic protein or non-protein, capable of emitting a signal These are known molecules of those complexes.

[0494] Preferably, in the presence of a reporter component initiator, in the vicinity of the first and second reporter components Therefore, the generated signal is selected from the group consisting of emission, fluorescence, and colorimetric change.

[0495] In some embodiments, luminescence is caused by luciferase, galactosidase, and lactamase. , a group consisting of any protein capable of luminescence in the presence of peroxidase or a suitable substrate It is produced by selected bioluminescent proteins.

[0496] A preferred combination of the first and second reporter components is U.S. Patent No. 8,283,1 This includes what is detailed in Specification No. 27, but the usefulness of the first and second reporter components These are by no means the only possible combinations.

[0497] In some embodiments, the screening method involves the phase of the first and second reporter components. By detecting the proximity of each other, candidate drugs can be identified as RAGE polypeptides and AT1R, etc. Certain coexisting G receptors, such as angiotensin receptors or specific chemokine receptors like CCR2. This further includes determining whether to modulate the interaction with PCR. Generally, This is because the proximity of the first and second reporter components is between the RAGE polypeptide and AT1R, etc. Certain symbiotic receptors, such as angiotensin receptors or specific chemokine receptors like CCR2 The proximity signal was altered by the regulation of the proximity candidate drug between the GPCR and the GPCR. It is sometimes achieved.

[0498] Angiotensin receptors such as AT1R or chemokine receptors such as CCR2, R Either or both of the AGE and certain coexisting GPCRs are in a soluble form or on the cell surface. It can manifest.

[0499] In some embodiments, an angiotensin receptor such as AT1R or a CCR2 such as RAGE and certain coexisting GPCRs, such as specific chemokine receptors, are located within a single membrane. They are either located within or partially within, or located on top of, for example, both are host cells. It is expressed on the surface.

[0500] In another embodiment of the present invention, an angiotensin receptor such as AT1R or CCR2, etc. Certain coexisting GPCRs, such as specific chemokine receptors, are complexes pre-formed at the cell membrane. It is assembled in advance along with RAGE.

[0501] In another embodiment of the present invention, an angiotensin receptor such as AT1R or CCR2, etc. Regarding AT1R, Ang II is a specific coexisting GPCR, such as a specific chemokine receptor. Alternatively, after activation of CCR2 by association with recognition ligands such as MCP-1, RAGE This triggers signal transduction involving the cytoplasmic tail.

[0502] In one embodiment of the present invention, activation of the cytoplasmic tail of RAGE is associated with its structural three-dimensional structure. This relates to changes in affinity for and / or binding partners.

[0503] In one embodiment of the present invention, the structural three-dimensional structure and / or bonding partners of RAGE Affinity monitoring is performed using RAGE ligands or specific activated coexisting GPCRs. R This occurs when the cytoplasmic tail of AGEs is mutated and / or cleaved.

[0504] In one embodiment of the present invention, the structural three-dimensional structure and / or affinity to the bonding partner Monitoring involves RAGE mediated by RAGE ligands or specific activated coexisting GPCRs. Inhibits RAGE binding and / or activation through ligand-independent RAGE activation. It occurs in the presence of drugs.

[0505] In one embodiment of the present invention, monitoring of the recruitment of binding partners is performed by RAGE ligand Alternatively, RAGE ligand-independent RAGE activation by specific activated coexisting GPCRs. This occurs before RAGE is activated.

[0506] One embodiment of the present invention relates to the cytoplasmic side of the signaling mediator and / or RAGE. Monitoring the recruitment and activation of binding partners to the tail is performed using RAGE ligands or specific RAGE ligand-independent RAGE activation by a constant activated coexisting GPCR This occurs after RAGE is activated.

[0507] One embodiment of the present invention involves using a RAGE ligand or a specific activated coexisting GPCR. RAGE ligand-independent RAGE activation leads to the binding partner of RAGE after activation. Monitoring of the mobilization of RAGE involves the binding and / or activation of RAGE by RAGE ligands. It occurs in the presence of inhibitory drugs.

[0508] Further embodiments of the present invention involve a candidate drug being used with an angiotensin receptor such as AT1R or This involves specific coexisting GPCRs, such as certain chemokine receptors like CCR2, which trigger RAGE ligaments. This modulates RAGE activation in an independent manner (through activation, inhibition, or other means). Regarding its capabilities, by detecting the modulation of signaling mediated by RAGE, This includes methods for leaning. Such methods involve measuring one or more of the following: This may include a step to measure standard NFκB activation. By monitoring the in vitro phosphorylation of substrates such as GST-IκBα The activity of IκB kinase (IKK); • Including phosphorylation / ubiquitination and / or degradation of IκB and / or IκB-α, Ik Detection of B degradation kinetics; • p65(Rel-A) analysis using antibodies, gel shift, EMSA, or mass spectrometry. Detection of phosphorylation / ubiquitination; • Transport of NFκB components / subunits such as p65 / phosphop65 from the cytoplasm to the nucleus / Detection of metastasis; • Detection of dimerization / complex formation of NFκB subunits; • Electrophoretic mobility shift assay or gel shift assay, SELEX, protein binding NFκB response elements / cosmetic elements, such as the use of a combined microarray or sequence-based approach. Activation by binding to immobilized DNA sequences / oligonucleotides containing NFκB binding Detection of sexual NFκB components / subunits; • Injection of NFκB into the promoters and enhancers of specific genes into DNA Chromatin immunoprecipitation (ChIP) assay for detecting tubular bonds; • In vitro kinase assay for NFκB kinase activity; Plasmid transduction, reporter cell lines, minicircles, retroviruses, lentils Using approaches such as Irus, LacZ Fluc, eGFP SEAP, NF- NFκB reporter assay via transgene expression of reporter constructs such as gluc Measurement of NFκB transcriptional activity using the following method; • Measurement of changes in the expression of downstream targets of NFκB (cytokines, growth factors, adhesion molecules and Mitochondrial anti-apoptotic genes, proteins, or functional agents obtained by real-time PCR (e.g., Issey) (The multifaceted nature of NFκB is reflected in its transcriptional targets, which currently number over 500.) Please note that this is being done (http: / / www.bu.edu / nf-kb / ge ne-resources / target-genes / , accessed August 2, 2017 Please refer to)); and • Polkadots activity in T cells, adhesion in endothelial cells, activation in leukocytes, or tumorigenesis. Measurement of functional or structural changes induced by NFκB-dependent signaling, etc.

[0509] As an addition or alternative, such methods measure NF by measuring one or more of the following: This may include measuring signals resulting from the non-standard action of -κB. • Detection of NIK (NFκB-induced kinase); • Detection of IKKα activation / phosphorylation; • Ability to autophosphorylate or phosphorylate substrates by performing kinase assays. Detection of NIK kinase activity by [method / tool]; • Generation of p52-containing NFκB dimers such as p52 / RelB; Detection of phospho-NFκB2p100 (Ser866 / 870); • Detection of the partial decomposition (called treatment) of precursor p100 to p52; • Detection of p52 / RelB transfer to the nucleus; • Detection of p52 / RelB binding to the κB site; Plasmid transduction, reporter cell lines, minicircles, retroviruses, or lentiform cell lines. Approaches using viruses, such as LacZ Fluc, eGFP SEAP, and NF NFκB reporter assay via transgene expression of reporter constructs such as -gluc Measurement of NFκB transcriptional activity using (i); • Non-standard NFκB assays by real-time PCR, protein expression, or functional assays. Measurement of changes in the expression of downstream targets of Gunal signaling (such as CXCL12).

[0510] In another embodiment, the present invention relates to AT1R by Ang II or CCR2 by MCP-1. After activation of a specific coexisting GPCR by a recognition ligand such as, or after the formation of a specific coexisting GPCR If it is actively active, it modulates RAGE ligand-independent RAGE activation (i.e., active (modulate by alteration, inhibition, or other means), and appropriately angiotensin receptors such as AT1R or It modulates specific coexisting GPCRs, such as certain chemokine receptors like CCR2, and / or RAGE polypeptides or modulators that regulate the RAGE signaling pathway (activation) We propose methods for identifying agents, inhibitors, allosteric modulators, or functional substitutes. Provides. In a preferred embodiment of the present invention, such modulators are AT1R and other AN Geotensin receptors or specific chemokine receptors such as CCR2, or RAGE or inhibitors of one or both of specific coexisting GPCRs or inhibitors of the RAGE signaling pathway In a particularly preferred embodiment of the present invention, the regulation of the RAGE signaling pathway is GqSig AT1R signaling pathways such as the Nal signaling pathway or CCR2 signaling pathways such as the Gi signaling pathway Unlike the regulation of classical coexisting GPCR signaling pathways such as signaling pathways, and / or occur to a significantly different degree. In a particularly preferred embodiment of the present invention, RAGE SIG Inhibition of the nal signaling pathway can lead to the AT1R signaling pathway such as the Gq signaling pathway or Gi Classical specific coexistence of GPCRs such as the CCR2 signaling pathway Unlike and / or greater than the inhibition of the Gunar transmission pathway.

[0511] <Structure> In related embodiments, the present invention relates to RAGE and an angiotensin receptor such as AT1R or This involves proximity between specific coexisting GPCRs, such as certain chemokine receptors like CCR2. This provides a construct system for identifying deducers.

[0512] In some embodiments, these constructs are operably connected to a first code sequence. A first construct comprising a regulatory sequence, wherein the first coding sequence is a RAGE polyp Nucleic acid sequence encoding polypeptide corresponding to the peptide and proximity signal or energy supply A first construct comprising a nucleic acid sequence encoding a donor molecule; and a second construct operable to the encoding sequence. A second construct comprising a regulatory array connected to the AT, wherein the second coding array is AT Angiotensin receptors such as 1R or specific chemokine receptors such as CCR2 Nucleic acid sequences encoding polypeptides corresponding to specific coexisting GPCRs and proximity signals or e A second construct comprising a nucleic acid sequence encoding an energy receptor molecule is included in a specific embodiment. So, the energy donor molecule is a bioluminescent or fluorescent molecule, and the energy acceptor molecule is It is a fluorescent receptor molecule.

[0513] In other embodiments, the construct system of the present invention is operably connected to a first code sequence. A first construct including a clause sequence, wherein the first coding sequence is an array such as AT1R. Certain coexisting GPCRs, such as otensin receptors or specific chemokine receptors like CCR2. Nucleic acid sequences encoding the corresponding polypeptide and proximity signal or energy donor components A first construct comprising a nucleic acid sequence encoding a child; and a second construct operably connected to the second coding sequence. A second construct comprising a continuous regulatory sequence, wherein the second coding sequence is RAGE Nucleic acid sequence encoding polypeptides corresponding to lipeptides and proximity signals or energy —Includes a second construct comprising a nucleic acid sequence encoding a receptor molecule. In certain embodiments, Energy donor molecules are bioluminescent or fluorescent molecules, and energy acceptor molecules are fluorescent It is a receptor molecule.

[0514] In other embodiments, the construct system of the present invention is operably connected to a first code sequence. A first construct including a clause sequence, wherein the first coding sequence is an array such as AT1R. Certain coexisting GPCRs, such as otensin receptors or specific chemokine receptors like CCR2. A first construct comprising a nucleic acid sequence encoding a polypeptide corresponding to ; and a second construct comprising a regulatory sequence operably linked to a second coding sequence, wherein the second coding sequence comprises a nucleic acid sequence encoding a polypeptide corresponding to the RAGE polypeptide, thereby comprising a second construct in which the RAGE polypeptide lacks one or more of the extracellular domains of the native sequence.

[0515] <Method for regulating RAGE ligand-independent RAGE activation> In related aspects, the present invention provides a method for regulating RAGE ligand-independent RAGE activation by a specific co-existing GPCR activated in cells or tissues of animals or of animal origin (which may or may not be human or of human origin), such as an angiotensin receptor such as AT1R or a specific chemokine receptor such as CCR2.

[0516] <Specific method for regulating RAGE ligand-independent RAGE activation> In another related aspect, the present invention particularly provides a method for regulating RAGE ligand-independent RAGE activation and subsequent intracellular downstream signaling pathways by a specific co-existing GPCR activated, such as an angiotensin receptor such as AT1R or a specific chemokine receptor such as CCR2. These methods include cleaving or mutating RAGE such that the RAGE ligand cannot bind to its extracellular domain or exposing the cell to a modulator that regulates the binding of the RAGE ligand to RAGE, thereby impairing the binding of the RAGE ligand to its extracellular domain.

[0517] In a preferred form of the present invention, the regulation of the RAGE ligand-independent signaling pathway is by R​​​​​​​​​​ Unlike and / or significantly greater than the regulation of the AGE ligand-dependent signaling pathway .

[0518] In a particularly preferred embodiment of the present invention, the inhibition of the RAGE ligand-independent signaling pathway is unlike and / or significantly greater than the inhibition of the RAGE ligand-dependent signaling pathway .

[0519] <Regulation of both RAGE ligand-dependent and RAGE ligand-independent RAGE activation method> In another related aspect, the present invention regulates RAGE ligand-independent RAGE activation by specific activated co-existing GPCRs and, in addition, inhibits the subsequent downstream signaling pathways in cells, tissues or animals by RAGE ligand-dependent RAGE activation by RAGE ligands (including AGE-modified proteins, lipids or DNA, members of the S100 calgranulin family of proteins, HMGB1, amyloid and Mac -1) and provides a method for doing so. In one embodiment of the present invention, these methods use a modulator as described herein, including a fragment, analog or derivative of the cytoplasmic tail of RAGE, instead of the cytoplasmic tail of RAGE, in a binding interaction to prevent the activation of both RAGE ligand-dependent activation of RAGE and RAGE ligand-independent RAGE activation by specific activated co-existing GPCRs. In one embodiment of the present invention, cells are exposed to an inhibitor that inhibits the binding of signaling elements to the cytoplasmic tail of RAGE, whereby RAGE-dependent signaling is impaired, and the activation of RAGE mediated by RAGE ligands and the activation of specific activity by specific activated co-existing GPCRs are both inhibited. .

[0520] In one aspect of the present invention, these methods include, in a binding interaction, preventing the activation of both RAGE ligand-dependent activation of RAGE and RAGE ligand-independent RAGE activation by specific activated co-existing GPCRs using a modulator as described herein, including a fragment, analog or derivative of the cytoplasmic tail of RAGE, instead of the cytoplasmic tail of RAGE. In one aspect of the present invention, RAGE-dependent signaling is impaired by exposing cells to an inhibitor that inhibits the binding of signaling elements to the cytoplasmic tail of RAGE, and the activation of RAGE mediated by RAGE ligands and the activation of specific activity by specific activated co-existing GPCRs are both inhibited. In one aspect of the present invention, cells are exposed to an inhibitor that inhibits the binding of signaling elements to the cytoplasmic tail of RAGE, whereby RAGE-dependent signaling is impaired, and the activation of RAGE mediated by RAGE ligands and the activation of specific activity by specific activated co-existing GPCRs are both inhibited. In one aspect of the present invention, cells are exposed to an inhibitor that inhibits the binding of signaling elements to the cytoplasmic tail of RAGE, whereby RAGE-dependent signaling is impaired, and the activation of RAGE mediated by RAGE ligands and the activation of specific activity Inhibition of both RAGE ligand-independent RAGE activation by a modified coexisting GPCR. It brings about.

[0521] In one aspect of the present invention, these methods use RAG instead of the transmembrane domain of RAGE. Modulators according to this specification, comprising fragments, analogs, or derivatives of the transmembrane domain of E. Using this, we investigated the RAGE ligand-dependent behavior of RAGE by specific activated coexisting GPCRs. To prevent activation of both sexual activation and RAGE ligand-independent RAGE activation. This includes. In one aspect of the present invention, the modulator is a transmembrane domain of RAGE or one thereof. The part and fragments of the extracellular domain of RAGE are included. In one aspect of the present invention, the modulator is This includes the transmembrane domain of RAGE or a portion thereof, and a fragment of the cytoplasmic tail of RAGE. In one aspect of the present invention, the modulator is the transmembrane domain of RAGE or a portion thereof, and This includes fragments of the extracellular domain of RAGE and fragments of the cytoplasmic tail of RAGE.

[0522] In one aspect of the present invention, RAGE ligand-independent activation by specific activated coexisting GPCRs is possible. The modulators of sexual RAGE activation are those with a length of 40 amino acids or less, and 20 amino acids or less. Fragments of the ligand-binding extradomain of RAGE, comprising 10 amino acids or less or 5 amino acids or less. It contains.

[0523] In one embodiment, inhibition of RAGE ligand-dependent activation of RAGE is performed on specific activated This occurs simultaneously with the inhibition of RAGE ligand-independent RAGE activation by coexisting GPCRs. .

[0524] In one embodiment, these methods involve RAGE or its analogues, fragments, or derivatives. RAGE such that the cytoplasmic tail or part thereof of wild-type RAGE becomes a non-functional substitute. This includes silencing, cleavage, modification, or mutation of RAGE ligand-dependent or RAGE ligand-dependent. Activation via any AGE ligand-independent pathway (such as the S391A-RAGE mutation) It is not converted, or it cannot promote downstream RAGE-dependent signaling, and therefore RAG Inhibits signaling that occurs through the cytoplasmic tail of E and RAGE-dependent signaling. do.

[0525] In one embodiment, these methods involve RAGE or its analogues, fragments, or derivatives. RAGE such that the transmembrane domain or part thereof of wild-type RAGE becomes a non-functional substitute. This includes silencing, cleavage, modification, or mutation of RAGE ligand-dependent or RAGE ligand-dependent. Neither of the AGE ligand-independent pathways is activated, nor is downstream RAGE It is unable to promote RAGE-dependent signaling, and therefore the cytoplasmic tail of RAGE and RAGE-dependent It inhibits signal transduction that occurs through residual signal transduction. In one aspect of the present invention, the module The rator is a fragment of the transmembrane domain or a part thereof of RAGE and the extracellular domain of RAGE. Including a fragment. In one aspect of the present invention, the modulator is the transmembrane domain of RAGE or its Includes a portion and a fragment of the cytoplasmic tail of RAGE. In one aspect of the present invention, a modulator This includes the transmembrane domain of RAGE or a part thereof, and a fragment of the extracellular domain of RAGE, and This includes fragments of the cytoplasmic tail of RAGE.

[0526] In one embodiment, RAGE ligand-independent RA by specific activated coexisting GPCRs GE activation modulators have lengths of 40 amino acids or less, 20 amino acids or less, and 10 amino acids or less. Contains fragments of the ligand-binding external domain of RAGE, which are 5 amino acids or less. ru.

[0527] In one embodiment, these methods involve RAGE or its analogues, fragments, or derivatives. This is a common element involved in signal transduction mediated by the cytoplasmic tail of RAGE. R (for adjusting PKCζ, Diaph1, MyD88, TIRAP, NFκB, etc.) Includes silencing, cleavage, modification, or mutation of AGEs. RAGE ligand-dependent or RA This is related to RAGE activation via one of the GE ligand-independent activation pathways.

[0528] In one embodiment, these methods involve RAGE ligand-dependent activation of RAGE (RAGE (For example, by modulators that regulate the binding of RAGE ligands to the extracellular domain.) In addition to modulators that regulate angiotensin receptors such as AT1R or CCR RAGE mediated by specific coexisting GPCRs, such as certain chemokine receptors like 2. This includes the use of modulators to adjust ligand-independent RAGE activation.

[0529] <While regulating RAGE-independent signaling via specific coexisting GPCRs, specific activity A method for regulating RAGE ligand-independent RAGE activation by modified coexisting GPCRs. > In one embodiment, the present invention relates to RAGE ligand independence by specific activated coexisting GPCRs. It not only regulates RAGE activation in the present state, but is also induced after activation by recognition ligands. This provides a method to regulate specific coexisting GPCR signaling pathways that are independent of RAGE.

[0530] In one embodiment, the present invention relates to RAGE ligand independence by specific activated coexisting GPCRs. It regulates RAGE activation in the present state, and is also induced after activation by the recognition ligand. This provides a method for modulating specific coexisting GPCR signaling pathways that are independent of RAGE.

[0531] In one form, a specific coexistence that is RAGE-independent is induced after activation by a recognition ligand. The GPCR signaling pathway involves Gq signaling such as AT1R, which is activated by Ang II. It is a non-transduction pathway. In another form, it is a RAGE-independent specific coexisting GPCR signaling pathway. The signaling pathway is the Gi signaling pathway, such as CCR2, which is activated by MCP-1. In another form, certain coexisting GPCR signaling pathways independent of RAGE are involved in β-arresting. This is a RAGE-mediated extracellular regulatory kinase (ERK) signaling pathway. In another form, it is RAGE-independent. The specific coexistence of GPCR signaling pathways involves intracellular signaling mediators (inositol). This is a change in (such as phosphate or calcium). [Brief explanation of the drawing]

[0532] [Figure 1A] Quantitative plaque area, expressed as the percentage of Sudan IV-stained aortic arch surface area after 4 weeks of Ang II (1 μg / kg / min) or vehicle-controlled infusion in male apoE-KO mice and AGER / apoE double knockout (DKO) mice. [Figure 1B]Expression of atherosclerosis-inducing mediators, including AGER itself, adhesion molecules (ICAM-1, VCAM-1), inflammatory cytokines and chemokines (TNFα, MCP-1, and IL-6), and macrophage markers (Mac-1 / Cd11b), as measured by real-time RT-PCR in aortic homogenates from apoE-KO mice and AGER / apoE-DKO mice after 4 weeks of Ang II (1 μg / kg / min) or vehicle-controlled infusion. [Figure 1C] (i) Plasma 8-hydroxydeoxyguanosine (8-OH-dG), a marker of oxidative DNA damage, and (ii) Markers of oxidative stress after 4 weeks of Ang II (1 μg / kg / min) or vehicle-controlled injection in apoE-KO mice and AGER / apoE-DKO mice, as predicted by induction of gene expression of NADPH oxidase subunits NOX-1 and NOX-4 in the aorta of apoE-KO mice and AGER / apoE-DKO mice, as predicted by real-time RT-PCR in aortic homogenate. [Figure 1D] (i) circulating plasma levels of S100A8 / A9 as measured by a commercially available ELISA; (ii) plasma AGE levels as measured by our proprietary ELISA; (iii) RAGE ligand expression, including circulating levels of methylglyoxal, an AGE precursor, as measured by HPLC in apoE-KO mice and AGER / apoE-DKO mice after 4 weeks of infusion of Ang II (1 μg / kg / min) or vehicle. [Figure 1E] Systolic blood pressure, measured by tail cuff plethysmography, after 4 weeks of Ang II (1 μg / kg / min) or vehicle-controlled infusion in apoE-KO mice and AGER / apoE-DKO mice. Data are mean ± SEM; n=8 per group, * indicates comparison with control apoE-KO mice, # indicates comparison with apoE-KO + Ang II, p<0.05. [Figure 2A]Quantitative plaque area, expressed as the percentage of Sudan IV-stained aortic arch surface area in apoE-KO mice and AGER / apoE-DKO mice after a 6-week diet of 0.05% (low) sodium or normal feed. [Figure 2B] Expression of atherosclerosis-inducing mediators, including AGER itself, adhesion molecules (ICAM-1, VCAM-1), inflammatory cytokines and chemokines (TNFα, MCP-1, and IL-6), and macrophage markers (Mac-1 / Cd11b), as measured by real-time RT-PCR in aortic homogenates of apoE-KO mice and AGER / apoE-DKO mice after 6 weeks of a 0.05% (low) sodium diet or normal diet. [Figure 2C] (i) Plasma 8-hydroxydeoxyguanosine (8-OH-dG), a marker of oxidative DNA damage, and (ii) Markers of oxidative stress in apoE-KO mice and AGER / apoE-DKO mice after 6 weeks of a 0.05% (low) sodium diet or normal diet, as estimated by induction of gene expression of NADPH oxidase subunits NOX-1 and NOX-4 in the aorta of apoE-KO mice and AGER / apoE-DKO mice, as estimated by real-time RT-PCR in aortic homogenate. [Figure 2D] Circulating levels of soluble MCP-1 and ICAM-1, measured by ELISA in apoE-KO mice and AGER / apoE-DKO mice exposed to a 0.05% (low) sodium diet or normal feed for 6 weeks. [Figure 2E] The number of labeled leukocytes adhering ex vivo to the aortic surface of apoE-KO mice and AGER / apoE-DKO mice one week prior to exposure to a low-sodium diet or normal feed, as measured by dynamic flow assay. [Figure 2F](i) circulating plasma levels of S100A8 / A9 as measured by a commercially available ELISA, (ii) plasma AGE levels as measured by our proprietary ELISA, and (iii) RAGE ligand expression, including circulating levels of methylglyoxal, an AGE precursor, as measured by HPLC in apoE-KO mice and AGER / apoE-DKO mice after a 6-week 0.05% (low) sodium diet or normal diet. [Figure 2G] Systolic blood pressure, measured by tail cuff plethysmography in apoE-KO mice and AGER / apoE-DKO mice after a 6-week diet of 0.05% (low) sodium or normal feed. [Figure 2H] Markers of RAAS activation, including (i) decreased sodium excretion, (ii) increased plasma renin activity, and (iii) increased plasma aldosterone levels, are measured by radioimmunoassay in apoE-KO mice and AGER / apoE-DKO mice after a 6-week 0.05% (low) sodium diet or normal diet. Data are mean ± SEM; n=8 per group. * indicates p<0.05 compared to apoE-KO mice on a normal diet. # indicates compared to apoE-KO mice with low sodium. [Figure 3A] Serum Ang II concentrations in apoE-KO mice and AGER / apoE-KO mice with or without genetic Ace2 deficiency, as measured by radioimmunoassay. [Figure 3B] Systolic blood pressure, measured by tail cuff plethysmography, in 18-week-old apoE-KO mice and AGER / apoE-KO mice with or without genetic Ace2 deficiency. [Figure 3C] Quantitative plaque area, expressed as the percentage of Sudan IV-stained aortic arch surface area, in 18-week-old apoE-KO mice and AGER / apoE-KO mice with or without genetic Ace2 deficiency. [Figure 3D]Aortic expression of atherosclerosis-inducing mediators, including AGER itself, adhesion molecules (ICAM-1, VCAM-1), inflammatory cytokines and chemokines (TNFα, MCP-1, and IL-6), and macrophage markers (Mac-1 / Cd11b), as measured by real-time RT-PCR in aortic homogenates from apoE-KO mice, in the presence or absence of Ace2 and / or RAGE. [Figure 3E] Oxidative stress in 18-week-old apoE-KO mice, Ace2 / apoE-DKO mice, AGER / apoE-DKO and Ace2 / AGER / apoE triple KO (TKO) mice, as estimated by plasma 8-hydroxydeoxyguanosine (8-OH-dG), a marker of oxidative DNA damage. [Figure 3F] (i) Circulating plasma levels of S100A8 / A9 as measured by a commercially available ELISA; (ii) RAGE ligand expression, including plasma AGE levels as measured by our proprietary ELISA in 18-week-old apoE-KO mice, Ace2 / apoE-DKO mice, AGER / apoE-DKO and Ace2 / AGER / apoE TKO mice. Data are mean ± SEM; n=8 per group; * indicates relative to apoE-KO control; # indicates relative to Ace2 / apoE-DKO mice. [Figure 4A] Aortic expression of atherosclerosis-inducing mediators, including AGER itself, adhesion molecules (ICAM-1, VCAM-1), inflammatory cytokines and chemokines (TNFα, MCP-1, and IL-6), and macrophage markers (Mac-1 / Cd11b), in apoE-KO mice and AGER / ApoE-DKO mice, measured by real-time RT-PCR in aortic homogenates after ex vivo exposure to Ang II or vehicle. Data are mean ± SEM; n=6 per group; * compared to untreated apoE-KO control; # compared to apoE-KO + Ang II; p<0.05. [Figure 4B]The number of labeled leukocytes adhering to the aortic surface of apoE-KO mice and AGER / apoE-DKO mice as a marker of endothelial activation after 4 hours of ex vivo exposure to Ang II (1 μM) or vehicle control, as measured by dynamic flow assay. Data are mean ± SEM; n=6 per group; * is against untreated apoE-KO control; # is AGER / apoE-DKO + Ang II compared to apoE-KO + Ang II; p<0.05. [Figure 4C] The number of labeled THP-1 monocytes attached to a monolayer of primary mouse aortic endothelial cells (PMAEC) from C57bl6 or AGER-KO mice, in or without pretreatment with Ang II (1 μM for 2 hours). [Figure 4D] Expression of atherosclerosis-inducing mediators, including AGER itself, key adhesion molecules (ICAM-1, VCAM-1), inflammatory cytokines and chemokines (TNFα and MCP-1), as measured by real-time RT-PCR in primary mouse aortic endothelial cells (PMAEC) from C57bl6 and PMAEC from AGER-KO mice after exposure to Ang II (1 μM) or vehicle controls. [Figure 4E] Markers of oxidative stress after exposure to Ang II or vehicle control in PMAEC from c57bl6 mice and AGER-KO mice, estimated by (i) induction of DCFH fluorescence in a flow chamber assay, and (ii) levels of the GTP-activated NADPH oxidase subunit, Rac-1, and (iii) levels of oxidized glutathione. [Figure 4F] Gene expression of markers of non-standard and standard signaling mediated by VCAM-1 and NFκB (CXCL12 and CXCL2, respectively) in monolayers of primary mouse aortic endothelial cells (PMAEC) from C57bl6 and AGER-KO mice after exposure to Ang II. PMAEC measured by real-time RT-PCR. TNFα is shown as a standard specific control. VCAM-1 is shown as a target-specific control replicating the data in Figure 4D. [Figure 4G]Expression of atherosclerosis-inducing mediators, including adhesion molecules (ICAM-1, VCAM-1) and inflammatory cytokines and chemokines (TNFα and MCP-1), in primary mouse aortic endothelial cells (PMAECs) from C57bl6 and AGER-KO mice treated with RAGE ligand, S100A8 / A9 (5 ng / mL), as measured by real-time RT-PCR. Data are mean ± SEM; n=6 per group; symbols * for untreated wild-type PMAECs; # for S100A8 / A9-treated wild-type PMAECs; p<0.05. [Figure 4H] Genetic expression of VCAM-1, a key adhesion protein in the PMAEC monolayer, was determined by real-time RT-PCR, after selective silencing or no alteration of RAGE or NFκB subunit p65 expression using siRNA (scrambled RNA control), followed by exposure to Ang II (1 μM) or RAGE ligand, S100A8 / A9 (5 ng / mL). [Figure 4I] Markers of Gq-mediated signaling induced after AT1R activation by Ang II (1 μM) in the monolayer of PMAEC from c57bl6 mice and AGER-KO mice, including (i) induction of inositol phosphate synthesis as predicted by IP-1, and (ii) downstream induction of the early growth response gene (EGR1). Data are mean ± SEM; n=6 per group; unless otherwise specified, * is relative to untreated wild-type control PMAEC, # is relative to Ang II-treated wild-type control, p<0.05. [Figure 5A] Induction of inositol phosphate synthesis in response to Ang II (1 μM), a marker of classical responsiveness to exogenous Ang II as estimated by IP-1 levels in CHO cells, in or without additional expression of full-length human RAGE, in the presence or absence of human AT1R expression. [Figure 5B]Induction of EGR1 expression in response to Ang II (1 μM), a marker of responsiveness to exogenous Ang II, which is presumed to be caused by downstream induction of the EGR1 gene in CHO cells, with or without additional expression of full-length human RAGE, in the presence or absence of human AT1R expression. [Figure 5C] (i) Chemiluminescent SEAP reporter gene assay; (ii) Induction of NFκB subunit p65 gene expression in the presence or absence of human AT1R expression in CHO cells with or without additional expression of full-length human RAGE; and (iii) NFκB activation after exposure to Ang II (1 μM), as measured after exposure to RAGE ligand S100A8 / A9 (5 ng / mL) as a control for the completeness of RAGE signaling in CHO cells. [Figure 5D] NFκB activation in AT1R-CHO cells after exposure to Ang II (1 μM) was measured by a chemiluminescent SEAP reporter gene assay for induction of NFκB subunit p65 gene expression and NFκB activity in the presence or absence of full-length human RAGE and N-terminal truncated mCherry-RAGE constructs. Data are mean ± SEM, n=6 per group, * indicates p<0.05 compared to vector (neo)-transduced AT1R-CHO. [Figure 5E] NFκB activation in AT1R-CHO after exposure to Ang II (1 μM), as estimated by chemiluminescent SEAP reporter gene assay, in the presence or absence of full-length human RAGE and C-deficient mCherry-RAGE constructs, and induction of NFκB subunit p65 gene expression and NFκB activity. Data are mean ± SEM, n=6 per group, * indicates p<0.05 compared to vector (neo)-transduced AT1R-CHO. [Figure 5F]NFκB activation in AT1R-CHO after exposure to S100A8 / A9 (5 ng / mL) or Ang II (1 μM), as estimated by induction of NFκB subunit p65 gene expression in the presence or absence of full-length human RAGE and N-terminal truncated mCherry-RAGE constructs. Data are mean ± SEM, n=6 per group, * indicates p<0.05 compared to vector (neo)-transduced AT1R-CHO. [Figure 5G] NFκB activation in AT1R-CHO after exposure to S100A8 / A9 (5 ng / mL) or Ang II (1 μM), as estimated by induction of NFκB subunit p65 gene expression in the presence or absence of full-length human RAGE and C-deficient mCherry-RAGE constructs. Data are mean ± SEM, n=6 per group, * indicates p<0.05 compared to vector (neo)-transduced AT1R-CHO. [Figure 5H] NFκB activation after exposure to Ang II (1 μM) in AT1R-CHO, as predicted by induction of NFκB subunit p65 gene expression in the presence of an N-terminal truncated RAGE construct not fused to mCherry. Data are mean ± SEM; n=6 per group; * indicates p<0.05 compared to untreated AT1R-CHO unless otherwise specified. [Figure 6A] RAGE neutralizing antibodies targeting the extracellular domain of RAGE (RAGEab) or decoy receptors with ligand-binding affinity (soluble RAGE22-331) inhibit the induction of pro-inflammatory signaling in RAGE-AT1R-CHO cells, mediated by RAGE ligand S100A8 / A9 but not by Ang II (1 μM), as can be inferred from the expression of NFκB subunit p65 measured by RT-PCR. Data are shown mean ± SEM; n=6 per group, * indicates p<0.05 compared to vehicle alone. [Figure 6B]RAGE neutralizing antibodies targeting the extracellular domain of RAGE (RAGEab) or decoy receptors with ligand-binding affinity (soluble RAGE22-331; sRAGE) do not inhibit the induction of pro-inflammatory signaling by Ang II (1 μM) in PMAEC from wild-type mice, as presumably by the induction of the major adhesion genes ICAM-1 and VCAM-1 and the inflammatory chemokine gene (MCP-1). Data from AGER-KO mice are shown as a negative control. Data are shown mean ± SEM; n=6 per group, * indicates control cells treated with vehicle alone (white bar), # indicates control cells treated with Ang II alone, p<0.05. [Figure 6C] RAGE neutralizing antibodies targeting the extracellular domain of RAGE (RAGEab) or decoy receptors with ligand-binding affinity (soluble RAGE22-331) inhibit the induction of pro-inflammatory signaling by RAGE ligand S100A8 / A9 in PMAEC from wild-type mice, as predicted by the induction of the major adhesion gene ICAM-1. Data are shown mean ± SEM; n=6 per group, * indicates control cells treated with vehicle alone (white bar), # indicates control cells treated with S100A8 / A9 alone, p<0.05. [Figure 7A] Induction of inflammatory signaling by RAGE ligand S100A8 / A9 (5 ng / ml; gray bar) or Ang II (1 μM; black bar) in AT1R-CHO cells expressing full-length wild-type RAGE22-404 or selected S391-RAGE22-404 mutants, as measured by induction of NFκB subunit p65 gene expression. Data show mean ± SEM; n=6-8 per group, * indicates p<0.05 compared to vehicle-treated AT1R-CHO cells expressing full-length RAGE. [Figure 7B]In AT1R-CHO cells, induction of pro-inflammatory signaling by RAGE ligand S100A8 / A9 (5 ng / ml) or Ang II (1 μM) was measured by induction of NFκB subunit p65 gene expression, including chimeric RAGE lacking phosphorylated motifs on the cytoplasmic tail other than S391 (chimeric RAGE; cRAGE), and S391-cRAGE mutants completely lacking any phosphorylated motifs on the cytoplasmic tail. Data are shown mean ± SEM; n=6-8 per group, * indicates comparison with vehicle-treated AT1R-CHO cells expressing full-length chimeric RAGE; p<0.05. [Figure 7C] Induction of pro-inflammatory signaling by Ang II (1 μM) in AT1R-CHO cells expressing full-length or N-terminal truncated S391A-RAGE mutants, as measured by induction of NFκB subunit p65 gene expression. Data are shown mean ± SEM; n=6-8 per group, * indicates p<0.05 compared to vector-transduced AT1R-CHO cells. [Figure 7D] Induction of pro-inflammatory signaling by Ang II (1 μM) in the presence of wild-type mCherry-RAGE362-404 in AT1R-CHO cells also expressing the S391-RAGE362-404 mutant, as measured by induction of NFκB subunit p65 gene expression. Data are shown mean ± SEM; n=6-8 per group, * indicates p<0.05 compared to vehicle control. [Figure 8A] The effect of selective suppression of MyD88 expression using siRNA or a scrambled control on the induction of RAGE ligand-dependent induction of inflammatory signaling by RAGE ligand S100A8 / A9 (5 ng / ml) in a monolayer of PMAEC from C57bl6 mice, as estimated by ICAM-1 expression measured by real-time RT-PCR. Selective suppression of p65 expression, another downstream mediator of RAGE signaling, using siRNA is shown as a positive control. [Figure 8B]The effect of selective suppression of MyD88 expression using siRNA or scrambled control in a monolayer of PMAEC from C57bl6 mice on the induction of RAGE ligand-independent induction of inflammatory signaling by Ang II (1 μM), as estimated by ICAM-1 expression measured by real-time RT-PCR. [Figure 8C] The effect of selective suppression of MyD88 expression in a monolayer of HMEC using siRNA or a scrambled control on the induction of RAGE ligand-independent induction of inflammatory signaling by Ang II (1 μM) in the presence and absence of RAGE362-404, as estimated by MCP-1 expression measured by real-time RT-PCR. Data are mean ± SEM; n=6-8 per group, * indicates p<0.05 compared to scrambled control. [Figure 9A] The effect of selective suppression of PKCζ using siRNA targeting the expression of a pseudosubstrate of PKCζ (iPKCz) or PKCζ (siPKCz), RAGE (siRAGE), or a scrambled control in a monolayer of PMAEC from C57bl6 mice on induction of RAGE ligand-dependent signaling by RAGE ligand S100A8 / A9, as predicted by ICAM-1 expression measured by real-time RT-PCR. [Figure 9B] The effect of selective suppression of PKCζ expression using siRNA targeting a pseudosubstrate of PKCζ (iPKCζ) or PKCζ (siPKCζ) on RAGE ligand-independent induction of inflammatory signaling by Ang II (1 μM) in a monolayer of PMAEC from C57bl6 mice. Columns 1 and 2 include scrambled siRNA controls. [Figure 9C]The effect of selective repression of PKCζ expression using a pseudosubstrate of PKCζ (PKCζi) on RAGE ligand-independent induction of p65 and PCNA by Ang II (1 μM) in CHO cells expressing cRAGE, which includes chimeric RAGE and S391Q-RAGE mutations (S319Q-cRAGE) lacking phosphorylated motifs on the cytoplasmic tail other than S391(cRAGE), as predicted by the gene expression of RelA / p65 and PCNA measured by real-time RT-PCR. [Figure 9D] The effect of selective suppression of PKCζ expression using siRNA or scrambled control in a monolayer of HMEC on the induction of RAGE ligand-independent induction of inflammatory signaling by Ang II (1 μM) in the presence and absence of RAGE362-404, as estimated by MCP-1 expression measured by real-time RT-PCR. Data are mean ± SEM; n=6-8 per group, * indicates p<0.05 compared to untreated control. [Figure 10A] The effect of selective suppression of Diaph1 expression using siRNA in a monolayer of PMAEC f...

Claims

1. An isolated or purified peptide that inhibits RAGE ligand-independent signaling, wherein the peptide is An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 390 to at least 379 of SEQ ID NO: 14, wherein the C-terminus of the peptide corresponds to residue 390 of SEQ ID NO: 14, and the amino acid corresponding to residue 379 of SEQ ID NO: 14 is Q or its conserved amino acid substitution. A peptide consisting of the following, isolated or purified.

2. An isolated or purified peptide according to claim 1, comprising an amino acid sequence that is at least 90% identical to a continuous amino acid sequence consisting of residues 390 to at least 379 of SEQ ID NO: 14, wherein the C-terminus of the peptide corresponds to residue 390 of SEQ ID NO: 14, and the amino acid corresponding to residue 379 of SEQ ID NO: 14 is Q, K, R, D, N, or E.

3. (i) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 22 to 390 of SEQ ID NO: 14; (ii) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 370 to 390 of SEQ ID NO: 14; (iii) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 370 to 390 of SEQ ID NO: 14, wherein the amino acid at the position corresponding to residue 379 of SEQ ID NO: 14 is K; (iv) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 370 to 390 of SEQ ID NO: 14, wherein the amino acid at the position corresponding to residue 388 of SEQ ID NO: 14 is A; (v) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 370 to 390 of SEQ ID NO: 14, wherein the amino acid at the position corresponding to residue 380 of SEQ ID NO: 14 is A; (vi) an amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 370 to 390 of SEQ ID NO: 14, wherein the amino acid at the position corresponding to residue 382 of SEQ ID NO: 14 is A; (vii) an amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 370 to 390 of SEQ ID NO: 14, wherein the amino acid at the position corresponding to residue 384 of SEQ ID NO: 14 is A; or (viiii) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 374 to 390 of SEQ ID NO: 14 The isolated or purified peptide according to claim 1, comprising the above.

4. The isolated or purified peptide according to claim 1, wherein the amino acid at the position corresponding to residue 388 of SEQ ID NO: 14 is not alanine.

5. The isolated or purified peptide according to claim 1, wherein the amino acid at the position corresponding to residue 388 of SEQ ID NO: 14 is leucine.

6. An isolated or purified peptide that inhibits RAGE ligand-independent signaling, wherein the peptide is (i) an amino acid sequence that is at least 90% identical to the consecutive amino acid sequence of SEQ ID NO: 14, and includes at least both residues 379 and 391 of SEQ ID NO: 14, The amino acid at the position corresponding to residue 379 of SEQ ID NO: 14 is Q or its conserved amino acid substitution, and A sequence in which the amino acid at the position corresponding to residue 391 of SEQ ID NO: 14 is not S; or (ii) An amino acid sequence that is at least 90% identical to the consecutive amino acid sequence of SEQ ID NO: 14, and includes at least both residues 379 and 391 of SEQ ID NO: 14, The amino acid at the position corresponding to residue 379 of sequence number 14 is not Q, and The amino acid at the position corresponding to residue 391 of sequence number 14 is not S, A peptide consisting of the following, isolated or purified.

7. The aforementioned peptide An amino acid sequence that is at least 90% identical to the consecutive amino acid sequence of SEQ ID NO: 14, and includes at least both residues 379 and 391 of SEQ ID NO: 14, The amino acid at the position corresponding to residue 379 of sequence number 14 is Q, K, R, D, N, or E, and The amino acid at the position corresponding to residue 391 of sequence number 14 is Y, C, V, R, N, K, H, G, F, E, D, or A. The isolated or purified peptide according to claim 6, comprising the above.

8. The isolated or purified peptide according to claim 6, wherein the amino acid at the position corresponding to residue 391 of SEQ ID NO: 14 is A.

9. The aforementioned peptide (i) an amino acid sequence that is at least 90% identical to the consecutive amino acid sequence consisting of residues 362 to 404 of Sequence ID No. 14, wherein the amino acid at the position corresponding to residue 391 is Y, C, V, R, N, K, H, G, F, E, D, or A; (ii) an amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 22 to 404 of Sequence ID No. 14, wherein the amino acid at the position corresponding to residue 391 is A, C, or E; or (iii) An amino acid sequence that is at least 90% identical to the continuous amino acid sequence consisting of residues 342 to 404 of SEQ ID NO: 14, wherein the amino acid at the position corresponding to residue 391 of SEQ ID NO: 14 is A. The isolated or purified peptide according to claim 6, comprising the above.

10. The isolated or purified peptide according to claim 6, wherein the amino acid at the position corresponding to residue 388 of SEQ ID NO: 14 is not alanine.

11. The isolated or purified peptide according to claim 6, wherein the amino acid at the position corresponding to residue 388 of SEQ ID NO: 14 is leucine.

12. An isolated or purified peptide according to any one of claims 1 to 11, (i) A reporter component selected from the group consisting of enzymes, luminescent or bioluminescent molecules, and fluorescent molecules, or (ii) Peptides used for affinity purification, peptides that guide fusion polypeptides into intracellular compartments of eukaryotic cells, or peptides that promote translocation of eukaryotic cell membranes. A fusion polypeptide consisting of and .

13. A nucleic acid comprising a nucleotide sequence encoding an isolated or purified peptide according to any one of claims 1 to 11.

14. A nucleic acid comprising a nucleotide sequence encoding the fusion polypeptide described in claim 12.

15. A pharmaceutical composition comprising a therapeutically effective amount of an isolated or purified peptide according to any one of claims 1 to 11.

16. A pharmaceutical composition comprising a therapeutically effective amount of the fusion polypeptide described in claim 12.

17. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid described in claim 13.

18. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid described in claim 14.

19. A pharmaceutical composition comprising a therapeutically effective amount of an isolated or purified peptide according to any one of claims 1 to 11, for treating, preventing or managing RAGE-related disorders in patients requiring such treatment, prevention or management.

20. A pharmaceutical composition comprising a therapeutically effective amount of the fusion polypeptide according to claim 12, for treating, preventing, or managing RAGE-related disorders in patients requiring such treatment, prevention, or management.

21. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid described in claim 13, for treating, preventing, or managing RAGE-related disorders in patients requiring such treatment, prevention, or management.

22. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid described in claim 14, for treating, preventing, or managing RAGE-related disorders in patients requiring such treatment, prevention, or management.

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