The study demonstrates the utility of RFdiffusion in designing binders for intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). RFdiffusion, a denoising diffusion probabilistic model, is fine-tuned to generate binders from only the target sequence, allowing for sampling of various conformations. The approach was applied to design binders for Amylin, C-peptide, and VP48, achieving Kds in the 3-100 nM range. The Amylin binder inhibits amyloid fibril formation and dissociates existing fibers, enabling mass spectrometry-based detection. For IDRs like G3bp1, common gamma chain (IL2RG), and prion, the approach generated binders with 10 to 100 nM affinity, colocalizing with the receptors in cells. The method is versatile, targeting a wide range of conformational preferences, and has potential applications in diagnostics, therapeutics, and scientific research.The study demonstrates the utility of RFdiffusion in designing binders for intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). RFdiffusion, a denoising diffusion probabilistic model, is fine-tuned to generate binders from only the target sequence, allowing for sampling of various conformations. The approach was applied to design binders for Amylin, C-peptide, and VP48, achieving Kds in the 3-100 nM range. The Amylin binder inhibits amyloid fibril formation and dissociates existing fibers, enabling mass spectrometry-based detection. For IDRs like G3bp1, common gamma chain (IL2RG), and prion, the approach generated binders with 10 to 100 nM affinity, colocalizing with the receptors in cells. The method is versatile, targeting a wide range of conformational preferences, and has potential applications in diagnostics, therapeutics, and scientific research.