Current Molecular Pharmacology - Volume 9, Issue 1, 2016

Among the 22 FKBP domains in the human genome, FKBP12.6 and the first FKBP domains (FK1) of FKBP51 and FKBP52 are evolutionarily and structurally most similar to the archetypical FKBP12. As such, the development of inhibitors with selectivity among these four FKBP domains poses a significant challenge for structure-based design. The pleiotropic effects of these FKBP domains in a range of signaling processes such as the regulation of ryanodine receptor calcium channels by FKBP12 and FKBP12.6 and steroid receptor regulation by the FK1 domains of FKBP51 and FKBP52 amply justify the efforts to develop selective therapies. In contrast to their close structural similarities, these four FKBP domains exhibit a substantial diversity in their conformational flexibility. A number of distinct conformational transitions have been characterized for FKBP12 spanning timeframes from 20 s to 10 ns and in each case these dynamics have been shown to markedly differ from the conformational behavior for one or more of the other three FKBP domains. Protein flexibilitybased inhibitor design could draw upon the transitions that are significantly populated in only one of the targeted proteins. Both the similarities and differences among these four proteins valuably inform the understanding of how dynamical effects propagate across the FKBP domains as well as potentially how such intramolecular transitions might couple to the larger scale transitions that are central to the signaling complexes in which these FKBP domains function.

FK506-binding proteins have been implicated in numerous human diseases suggesting novel therapeutic opportunities. In particular, the large FKBP51 has emerged as an important regulator of the stress-coping system and as an established risk factor for stress-related disorders. The principal druggabilty of FKBPs is evidenced by the prototypical high affinity ligands FK506 and rapamycin but the development of more refined and selective chemical probes for FKBPs has been challenging. In this review we summarize recent advances in the development of FKBP ligands, which cumulated in the first highly selective ligands for FKBP51. The best ligand SAFit2 allowed the proof-of-concept in mice for FKBP51 inhibitors as potentially novel antidepressants. Finally, we discuss pending issues that need to be addressed for the further development of FKBP51-directed drugs.

Immunophilins consist of a family of highly conserved proteins which possess binding abilities to immunosuppressive drugs. Cyclophilins (Cyps) and FK506-binding proteins (FKBP) are family proteins collectively referred as immunophilins. Most Cyps and FKBP family members catalyse peptidyl-prolyl cis/trans isomerase (PPIase) mediated reactions and form binary complexes with their ligands cyclosporine A and FK506. Immunophilins are also involved in key biochemical processes including protein folding, receptor signalling, protein trafficking, and transcription and exhibit versatile biological functions, when complexed with their ligands. Therapeutic implications of immunophilins and effects of their ligands in neurodegenerative disorders, cancer, and infectious diseases have been accumulating in recent years. This review focuses on molecular characteristics of the canonical and non-canonical immunophilin family members from human and Plasmodium falciparum and P. vivax, recent progress on immunophilin inhibitor development, and future perspectives of structure-based design of non-immunosuppressive immunophilin ligands with potential pharmacological activities against infectious diseases.

FK506 binding proteins (FKBPs) are a family of highly conserved proteins in eukaryotes. The prototype of this protein family, FKBP12, is the binding partner for immunosuppressive drugs FK506 and rapamycin. FKBP12 functions as a cis/trans peptidyl prolyl isomerase (PPIase) that catalyzes interconversion between prolyl cis/trans conformations. Members of the FKBP family contain one or several PPIase domains, which do not always exhibit PPIase activity yet are all essential for their function. FKBPs are involved in diverse cellular functions including protein folding, cellular signaling, apoptosis and transcription. They elicit their function through direct binding and altering conformation of their target proteins, hence acting as molecular switches. In this review, we provide a general summary for the structures and diverse functions of FKBPs found in mammalian cells.

The steroid receptor-associated TPR cochaperones FKBP51, FKBP52, CyP40 and PP5 have non-redundant roles in steroid receptor function that impact steroid hormone-binding affinity, nucleocyoplasmic shuttling and transcriptional activation of target genes in a tissue-specific manner. Aberrant expression of these TPR immunophilins has the potential to cause steroid-based diseases, including breast and prostate cancer, diabetes and metabolic disorders, male and female infertility and major depressive and neurodegenerative disorders. This review summaries the function of these proteins as cochaperones in steroid receptor-Hsp90 complexes and elaborates on their role in alternative, Hsp90-dependent and -independent signalling pathways not involving steroid receptors. The review also extensively covers current knowledge of the link between the steroid receptor-associated immunophilins and human disease. An improved understanding of their mechanisms of action has revealed opportunities for molecular therapies to enhance or inhibit cellular processes under their control that contribute both to human health and disease.