Chemical Approaches for 'Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins.

Drug Discovery;Medicinal Chemistry;Undruggable Targets;Small Heat Shock Proteins;Pharmacological Chaperones;Protein Misfolding;Chemistry;Science;Medicinal Chemistry

Makley, Leah NicoleCierpicki, Tomasz ;

University of Michigan

关键词: Drug Discovery;    Medicinal Chemistry;    Undruggable Targets;    Small Heat Shock Proteins;    Pharmacological Chaperones;    Protein Misfolding;    Chemistry;    Science;    Medicinal Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/109032/makleyln_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Small heat shock proteins (sHSPs) are molecular chaperones that protect against protein aggregation in response to stress.These chaperones have been linked to a number of protein misfolding diseases, including neurodegenerative disorders and cataracts. However, sHSPs are considered ;;undruggable” because they lack enzymatic activity or obvious ligand-binding sites. Thus, sHSPs are emblematic of potential drug targets emerging from large-scale genetic efforts. They are clearly linked to disease, yet it is not clear how to develop drug-small molecules to act on this knowledge. In this thesis work, I employed a number of high throughput biophysical approaches to discover cryptic binding sites on two sHSPs: Hsp27 and alphaB-crystallin (cryAB). Using a multifaceted approach involving computational approaches, differential scanning fluorimetry, fragment-based NMR screening and rational design, three unanticipated binding sites were discovered. Medicinal chemistry and structural efforts yielded four classes of small molecules, with representatives that bind each of the three cryptic pockets. One of these chemical series was developed as a potential new therapeutic for the topical treatment of cataract. These molecules bind the native dimer of cryAB and promote its chaperone functions, reversing cataracts in mouse and human lens models. Another series binds to a region of Hsp27 that is important for its interactions with the Hsp70 class of chaperones, showing promise as a chemical probe for understanding how chaperones regulate protein homeostasis. This thesis work has significantly advanced our knowledge of sHSP ;;druggability’ and revealed at least three binding sites for further development. Moreover, these efforts represent a detailed, head-to-head comparison of modern HTS methods to discover ligands for cryptic binding sites. The strengths and weaknesses of these approaches are important in designing screening campaigns for other ;;undruggable’ targets emerging from genetic studies.