FKBP12-binding domain analogues of FK506 are potent, nonimmunosuppressive neurotrophic agents in vitro and promote recovery in a mouse model of parkinson's disease

Hamilton, Gregory S.; Huang, Wei; Connolly, Maureen A.; Ross, Douglas T.; Guo, Hong; Valentine, Heather; Suzdak, Peter D.; Steiner, Joseph P.

doi:10.1016/s0960-894x(97)00304-1

Cited by 47 publications

(25 citation statements)

References 19 publications

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“…Several studies applying a wide range of animal models that mimick Parkinson's disease (PD), dementia, stroke and nerve damage have revealed that FKBP activity is a major factor in neuronal cell death and signaling [61][62][63][64][65][66][67][68][69]. FK506 administration resulted in protection against ischemic brain injury [70], prevention and modulation of long-term depression (LTD) [71] as well as long-term potentiation (LTP) [72], blocking of Nmethyl-D-aspartate (NMDA)-receptor desensitization [73], alteration in neuro-transmitter release [74], and attenuation of glutamate neurotoxicity ex vivo [75].…”

Section: Biological Relevance Of Fkbp Fkbp Function In Neuronal Signamentioning

confidence: 99%

Insights into Immunophilin Structure and Function

Lücke¹,

Weiwad

2011

CMC

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The immunophilins are proteins which are capable of influencing the immune response in combination with an immunosuppressive drug. Their natural function, however, is mainly the cis/trans isomerization of peptidyl-prolyl bonds in other proteins. This review lists all immunophilin structure coordinates currently available in the RCSB protein data bank and highlights the key active-site factors that define their catalytic and immunological action. In addition, an overview of biologically-relevant functions is provided for various immunophilin members.

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Section: Biological Relevance Of Fkbp Fkbp Function In Neuronal Signamentioning

confidence: 99%

Insights into Immunophilin Structure and Function

Lücke¹,

Weiwad

2011

CMC

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“…FK506 and FK520 also accelerate the rate of nerve regeneration (Gold, 2000;Hamilton and Thomas, 2000), being very potent in promoting neurite outgrowth in PC12 cells, SH-SY5Y cells, and primary neuronal cultures (Lyons et al, 1994;Gold et al, 1999). The neurotrophic property of these compounds has been established in a variety of animal models (for review, see Gold, 2000), including, sciatic nerve injury (Gold et al, 1994;Archibald et al, 1999;Doolabh and Mackinnon, 1999;Lee et al, 2000), spinal cord injury (Madsen et al, 1998;Wang and Gold, 1999), and toxic-chemical models of Parkinson's disease (Hamilton et al, 1997;Steiner et al, 1997b;Costantini et al, 1998;Emborg et al, 2001). Nevertheless, for treatment of neurodegenerative diseases, it would clearly be necessary to reduce or eliminate the immunosuppressive effects of these drugs.…”

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confidence: 99%

Genetically Engineered Analogs of Ascomycin for Nerve Regeneration

Revill¹,

Voda²,

Reeves³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/ 520-calcineurin ternary complex. They also have calcineurinindependent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13-and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13-and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.

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“…It was obvious that FK506 itself could not be used as an effective drug for treating neurodegenerative disease, since it possesses immunosuppressant activity. Fortunately, further studies showed that the neurotropic activity of FK506 was only relative to its binding domain [9][10][11] . In the present research, we hoped that small organic molecules could be designed based on the structural feature of FK506 binding to FKBP12.…”

Section: Design and Synthesis Of Compoundsmentioning

confidence: 99%

Drug discovery based on the structure of FKBP12: Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

et al. 2007

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By choosing neuroimmunophilin FKBP12 as a therapeutical target, we have attempted to discover a new structural drug for treating neurodegenerative disease. This drug should possess neurotrophic activity and not affect the immune system. Based on the crystal structure of FKBP12, FK506 and Calcineurin complex, a series of small organic molecules were designed. These molecules were to have the ability of binding to FKBP12 in a virtual screening. By using a solution parallel synthetic method, these compounds were synthesized. The neuroprotective and neuroregenerative activities of these compounds were evaluated by binding assays, PC12 cells survival and neurite outgrowth model, chick dorsal root ganglion cultures (DRG) and 6-OHDA lesioned mice sympathetic nerve endings model. The evaluation results of these compounds showed that compound N308 has great promise as a candidate for a neuroprotective and neuroregenerative agent.FKBP12, L-1,4-thiazane-3-carboxylic acid derivatives, design synthesis neurotrophic activity It remains an important challenge to discover an effective drug for treating neurodegenerative disease. Neuroimmunophilin FKBPs (FK506-binding proteins), which were found in the early 1990's, opened a new promise for discovery and development of drugs in the treatment of neurodegenerative disease [1,2] . At present, one of the neuroimmunophilin ligands, GPI-1485, had completed Phase II clinical trial as a candidate drug for treating Parkinson′s disease. It is planned that the product could be registered in 2009, following completion of Phase III studies (http://www.guilfordpharm.com/licensing/out/NIL. pdf). We have attempted to discover a new structural drug for treating neurodegenerative disease based on the structure of FKBP12 (a member of FK-506 binding proteins). Herein, we report the design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin FKBP12 ligands.

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FKBP12-binding domain analogues of FK506 are potent, nonimmunosuppressive neurotrophic agents in vitro and promote recovery in a mouse model of parkinson's disease

Cited by 47 publications

References 19 publications

Insights into Immunophilin Structure and Function

Insights into Immunophilin Structure and Function

Genetically Engineered Analogs of Ascomycin for Nerve Regeneration

Drug discovery based on the structure of FKBP12: Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

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