**6. Conclusion and Perspectives**

The pharmacological strategies developed so far (and reviewed here) that target IDPs can be separated as binding directly to IDPs and hampering their aggregation by keeping them in the interaction incompetent conformation; interacting with the IDP and promoting the stabilization of non-toxic/ non-amyloidogenic oligometric species; and interacting with the amyloidogenic protein and greatly accelerating its aggregation to minimize the period of toxic oligomer formation [338]. Still, as we described here, there are many pathways acting on IDP control, and these are still unexplored targets for pharmaceutical interference. As the binding mechanisms of IDPs are being better described from a physical chemical standpoint [339,340], it is becoming clear that for candidate molecules to act on IDPs they must deviate from traditional prediction rules for drug-likeness [319,320]. One standout feature of IDP ligands is that they are larger and more three-dimensional than traditional drugs [341]. Adding another layer of complexity to this scenario, some proteins are shown to be conditionally unfolded [342], being disordered only under specific conditions.

Despite being abundant in eukaryotes, in which IDPs have evolutionarily conserved interaction partners [343], the occurrence of disorder in proteins from other organisms is being described. It includes the description of IDPs in Trypanosomatid parasites [344] and in some paramyxoviruses, including measles, Nipah and Hendra viruses [345]. These proteins constitute prospective targets for drug design endeavors, as was also observed for multiple disordered targets in prostate cancer [346]. Furthermore, recent evaluations indicate that IDP-targeted drug development may not be irreconcilable with structure-based drug design [347].

The development of drugs specifically tailored for IDPs is still in its infancy. As with the whole pipeline for drug discovery, there has been continuous progress in this area, and as we proposed in this work, there are many untapped pathways and unexplored targets regarding these proteins. As the biophysical techniques advance to catch up with the diversity of disordered behaviors in proteins, one can expect major developments in this front. Taking the limited but solid cases of success in IDP-specific drug design, we may face a future in which target disorder may be taken as the rule and not the exception.

**Author Contributions:** Conceptualization, C.R.C. and R.L.-B.; Writing—Original Draft Preparation, A.H.S.M., F.C.L., E.O.J., C.R.C., and R.L.-B.; Writing—Review & Editing, C.R.C. and R.L.-B.; Funding Acquisition, C.R.C.

**Funding:** The authors of this work have been funded by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES and Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.

**Conflicts of Interest:** The authors declare no conflict of interest.
