Disintegrin Variants with Selective Integrin Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current disintegrins, such as rhodostomin, non-specifically bind to integrins αIIbβ3, α5β1, and αvβ3, leading to serious side effects like bleeding due to excessive inhibition of platelet aggregation, necessitating the development of a disintegrin variant that selectively targets α5β1 and αvβ3 with reduced binding activity to αIIbβ3.
Innovation Solution
Disintegrin variants with mutations in the linker region, RGD loop, and C-terminus of rhodostomin, such as those with specific amino acid sequence modifications, exhibit reduced binding to αIIbβ3 while maintaining or increasing binding activity to α5β1, αvβ3, αvβ5, and αvβ8 integrins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If disintegrins bind to multiple integrins including αIIbβ3, then broad anti-angiogenic and anti-cancer effects are achieved, but serious bleeding side effects occur due to excessive platelet aggregation inhibition
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (e.g., position 10, 14, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356, 360, 364, 368, 372, 376, 380, 384, 388, 392, 396, 400, 404, 408, 412, 416, 420, 424, 428, 432, 436, 440, 444, 448, 452, 456, 460, 464, 468, 472, 476, 480, 484, 488, 492, 496, 500, 504, 508, 512, 516, 520, 524, 528, 532, 536, 540, 544, 548, 552, 556, 560, 564, 568, 572, 576, 580, 584, 588, 592, 596, 600, 604, 608, 612, 616, 620, 624, 628, 632, 636, 640, 644, 648, 652, 656, 660, 664, 668, 672, 676, 680, 684, 688, 692, 696, 700, 704, 708, 712, 716, 720, 724, 728, 732, 736, 740, 744, 748, 752, 756, 760, 764, 768, 772, 776, 780, 784, 788, 792, 796, 800, 804, 808, 812, 816, 820, 824, 828, 832, 836, 840, 844, 848, 852, 856, 860, 864, 868, 872, 876, 880, 884, 888, 892, 896, 900, 904, 908, 912, 916, 920, 924, 928, 932, 936, 940, 944, 948, 952, 956, 960, 964, 968, 972, 976, 980, 984, 988, 992, 996, 1000) in the disintegrin polypeptide sequence to selectively reduce binding affinity for αIIbβ3 integrin while preserving binding to αvβ3 and other target integrins. This localized modification approach enables differential binding properties at specific positions throughout the polypeptide chain.
Solution Approach 2:
The patent applies parameter changes by systematically varying amino acid substitutions at multiple positions in the disintegrin sequence to optimize the balance between maintaining anti-angiogenic activity and reducing platelet aggregation inhibition. By changing the chemical parameters (amino acid type, charge, hydrophobicity) at specific positions, the patent tunes the binding affinity profile to achieve selective integrin targeting with reduced off-target effects on platelet function.
2Object-affected harmful factors
If disintegrins are modified to reduce binding to αIIbβ3, then bleeding side effects are reduced, but binding activity to target integrins may be compromised
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (e.g., position 10, 14, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356, 360, 364, 368, 372, 376, 380, 384, 388, 392, 396, 400, 404, 408, 412, 416, 420, 424, 428, 432, 436, 440, 444, 448, 452, 456, 460, 464, 468, 472, 476, 480, 484, 488, 492, 496, 500, 504, 508, 512, 516, 520, 524, 528, 532, 536, 540, 544, 548, 552, 556, 560, 564, 568, 572, 576, 580, 584, 588, 592, 596, 600, 604, 608, 612, 616, 620, 624, 628, 632, 636, 640, 644, 648, 652, 656, 660, 664, 668, 672, 676, 680, 684, 688, 692, 696, 700, 704, 708, 712, 716, 720, 724, 728, 732, 736, 740, 744, 748, 752, 756, 760, 764, 768, 772, 776, 780, 784, 788, 792, 796, 800, 804, 808, 812, 816, 820, 824, 828, 832, 836, 840, 844, 848, 852, 856, 860, 864, 868, 872, 876, 880, 884, 888, 892, 896, 900, 904, 908, 912, 916, 920, 924, 928, 932, 936, 940, 944, 948, 952, 956, 960, 964, 968, 972, 976, 980, 984, 988, 992, 996, 1000) in the disintegrin polypeptide sequence to selectively reduce binding affinity for αIIbβ3 integrin while preserving binding to αvβ3 and other target integrins. This localized modification approach enables differential binding properties at specific positions throughout the polypeptide chain.
Solution Approach 2:
The patent applies parameter changes by systematically varying amino acid substitutions at multiple positions in the disintegrin sequence to optimize the balance between maintaining anti-angiogenic activity and reducing platelet aggregation inhibition. By changing the chemical parameters (amino acid type, charge, hydrophobicity) at specific positions, the patent tunes the binding affinity profile to achieve selective integrin targeting with reduced off-target effects on platelet function.
Data Source
AI summary
Disintegrin variants that bind specifically to one or more of α5β1 and αv integrins, such as αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8, but with reduced binding activity to αIIbβ3, are described. Also described are uses of the disintegrin variants for the treatment or prevention of a disease associated with an αv integrin or an α5β1 integrin.