https://www.cell.com/cell/pdf/0092-8674(94)90570-3.pdf

RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs.

Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

https://www.nejm.org/doi/pdf/10.1056/NEJMra033540

Immunosuppressive Drugs for Kidney Transplantation

FK-506, a novel immunosuppressant, has been isolated from the fermentation broth of Streptomyces tsukubaenis No. 9993 as colorless prism and the molecular formula was determined as C44H69NO12.H2O. The compound suppressed immune responses in vitro and in vivo with mice. This immunosuppressive effect was more potent than that of ciclosporin.

FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.

Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.

The exploration of macrocycles for drug discovery--an underexploited structural class.

Genome and expressed sequence tag projects are rapidly cataloguing and cloning the genes of higher organisms, including humans. An emerging challenge is to rapidly uncover the functions of genes and to identify gene products with desired properties. We have developed a microarray-driven gene expression system for the functional analysis of many gene products in parallel. Mammalian cells are cultured on a glass slide printed in defined locations with different DNAs. Cells growing on the printed areas take up the DNA, creating spots of localized transfection within a lawn of non-transfected cells. By printing sets of complementary DNAs cloned in expression vectors, we make microarrays whose features are clusters of live cells that express a defined cDNA at each location. Here we demonstrate two uses for our approach: as an alternative to protein microarrays for the identification of drug targets, and as an expression cloning system for the discovery of gene products that alter cellular physiology. By screening transfected cell microarrays expressing 192 different cDNAs, we identified proteins involved in tyrosine kinase signalling, apoptosis and cell adhesion, and with distinct subcellular distributions.

Microarrays of cells expressing defined cDNAs

The immuno-pharmacological profile of a novel immunosuppressive agent, FK-506 produced by a streptomycete, is presented here. We proceeded to test the effect of the agent on various in vitro immune systems. It showed that mixed lymphocyte reaction, cytotoxic T cell generation, the production of T cell-derived soluble mediators such as interleukin 2 (IL-2), interleukin 3 and gamma-interferon and the expression of the IL-2 receptor were suppressed by this agent. The IC50 values of FK-506 and ciclosporin (CS) in all tests were approximately 0.1nM and 10nM, respectively. Therefore, the novel agent, FK-506 suppressed in vitro immune systems at about hundred times lower concentration than CS.

https://www.jstage.jst.go.jp/article/antibiotics1968/40/9/40_9_1249/_pdf

FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro.

FR-900520 and FR-900523, novel neutral macrolide immunosuppressants, were isolated from the cultured broth of Streptomyces hygroscopicus subsp. yakushimaensis No. 7238. Their molecular formulae were determined as C43H69NO12 and C42H67NO12, respectively. The compounds suppressed immune response in vitro. IC50 values of FR-900520 and FR900523 for mouse mixed lymphocyte reaction were 0.55 nM and 1.6nM, respectively. FR900520, the major component, clealy prolonged skin allograft survival in rats.

FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics.

WS009 A and B novel endothelin receptor antagonists, have been isolated from the fermentation broth of Streptomyces sp. No. 89009. These antagonists were purified from the culture filtrate followed by Diaion SP-207, DEAE Toyopearl column chromatography and HPLC. WS009 A and B showed selective activity in an endothelin receptor binding assay with IC50 of 5.8 x 10(-6) M and 6.7 x 10(-7) M, respectively. On the basis of spectroscopic and chemical evidence, the structures of WS009 A and B have been established as 1 and 3, and are highly hydroxylated benz[a]anthraquinone chromophores.

WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

WS-7338, produced by Streptomyces sp. No. 7338, was found to be a competitive and specific antagonist against ET-1 receptors in in vitro studies and WS-7338 B is also active in vivo. Furthermore, WS-7338 B was a specific antagonist for vascular ET-1 receptors (ETA receptors) and significantly prevented the accumulation of intracellular inositol 1, 4, 5-triphosphate (IP3) in endothelin treated rat aorta tissues.

WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. III. Structures of WS-7338 A, B, C and D and total synthesis of WS-7338 B

WS009 A and B novel endothelin receptor antagonists, have been isolated from the fermentation broth of Streptomyces sp. No. 89009. These antagonists were purified from the culture filtrate followed by Diaion SP-207, DEAE Toyopearl column chromatography and HPLC. WS009 A and B showed selective activity in an endothelin receptor binding assay with IC50 of 5.8 × 10-6M and 6.7 × 10-7M, respectively. On the basis of spectroscopic and chemical evidence, the structures of WS009 A and B have been established as 1 and 3, and are highly hydroxylated benz[a]anthraquinone chromophores.

Susumu Miyata

Papers

FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro.

FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics.

WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. III. Structures of WS-7338 A, B, C and D and total synthesis of WS-7338 B

WS009 A AND B, NEW ENDOTHELIN RECEPTOR ANTAGONISTS ISOLATED FROM Streptomyces sp. No. 89009