Drug discovery targeting heme-based sensors and their coupled activities

• Published in: Journal of inorganic biochemistry Vol. 167; pp. 12 - 20
• Main Authors: Sousa, Eduardo Henrique Silva, Lopes, Luiz Gonzaga de França, Gonzalez, Gonzalo, Gilles-Gonzalez, Marie-Alda
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2017
• Subjects: Animals; Anti-Bacterial Agents - analysis; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Biosensing Techniques - methods; Drug discovery; Drug Discovery - methods; Heme; Heme-based sensor; Histidine protein kinase; Humans; Mycobacterium tuberculosis; Nuclear receptor; Nucleotide cyclase; Phosphodiesterase; Soluble Guanylyl Cyclase - chemistry; Histidine protein kinase; Nuclear receptor; Drug discovery; Heme-based sensor; Nucleotide cyclase; Phosphodiesterase
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.11.022

Heme-based sensors have emerged during the last 20years as being a large family of proteins that occur in all kingdoms of life. A myriad of biological adaptations are associated with these sensors, which include vasodilation, bacterial virulence, dormancy, chemotaxis, biofilm formation, among others. Due to the key activities regulated by these proteins along with many other systems that use similar output domains, there is a growing interest in developing small molecules as their regulators. Here, we review the development of potential activators and inhibitors for many of these systems, including human soluble guanylate cyclase, c-di-GMP-related enzymes, Mycobacterium tuberculosis DevR/DevS/DosT (differentially expressed in virulent strain response regulator/sensor/dormancysurvival sensorT), the Rev-erb-α and β nuclear receptor, among others. The possible roles of these molecules as biochemical tools, therapeutic agents, and novel antibiotics are critically examined.
Scientists ponder how to design small molecules that target heme-based sensor proteins, including the human soluble guanylate cyclase, Rev-erb α and β, bacterial cyclases and phosphodiesterases for c-di-GMP. This work could lead to new agents for pest control, drugs such as novel antibiotics, cardiovascular agents, and medications for mood disorders. [Display omitted]
•Update on drug discovery to target medically relevant heme-based sensor proteins•Strategies for targeting protein domains are discussed and their potential showed•Regulators of soluble guanylate cyclase are described and their potential highlighted•Perspectives on metabolic/mood disorder therapy using Rev-erb as a sensor target•Molecules targeting c-di-GMP-related enzymes and histidine kinases as likely antibiotics