Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease

Bratkowski, Matthew; Burdett, Thomas C.; Danao, Jean; Wang, Xidao; Mathur, Prakhyat; Gu, Wei; Beckstead, Jennifer A.; Talreja, Santosh; Yang, Yusan; Danko, Gregory; Park, Jae Hong; Walton, Mary; Brown, Sean P.; Tegley, Christopher M.; Joseph, Prem Raj B.; Reynolds, Charles H.; Sambashivan, Shilpa

doi:10.1016/j.neuron.2022.08.017

Cited by 33 publications

(28 citation statements)

References 62 publications

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“…This binding mode is supported by cryo-EM data, where mechanism-based inhibitors are bound in the active site; , the inhibitor is formed when the free base “pro-drug” participates in the base exchange reaction with NAD + and remains bound to the enzyme active site. In these structures, the catalytic glutamate hydrogen bonds with the hydroxyls of the core ADPR scaffold common to the inhibitors in these structures. , Because these inhibitors are derived from NAD + and are formed in the active site, it is highly likely that the binding mode of these inhibitory ADPR adducts reflects the binding mode of the endogenous substrate NAD + . Notably, these structures were determined by two independent groups.…”

Section: Discussionmentioning

confidence: 77%

“…In this model, the catalytic glutamate stabilizes the intermediate by electrostatic interactions and/or by hydrogen bonding with the hydroxyls of the nicotinamide-ribosyl moiety to promote nicotinamide leaving. This binding mode is supported by cryo-EM data, where mechanism-based inhibitors are bound in the active site; 8,22 the inhibitor is formed when the free base "prodrug" participates in the base exchange reaction with NAD + and remains bound to the enzyme active site. In these structures, the catalytic glutamate hydrogen bonds with the hydroxyls of the core ADPR scaffold common to the inhibitors in these structures.…”

Section: ■ Discussionmentioning

confidence: 80%

“…In these structures, the catalytic glutamate hydrogen bonds with the hydroxyls of the core ADPR scaffold common to the inhibitors in these structures. 8,22 Because these inhibitors are derived from NAD + and are formed in the active site, it is highly likely that the binding mode of these inhibitory ADPR adducts reflects the binding mode of the endogenous substrate NAD + . Notably, these structures were determined by two independent groups.…”

Section: ■ Discussionmentioning

confidence: 99%

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SARM1, an Enzyme Involved in Axon Degeneration, Catalyzes Multiple Activities through a Ternary Complex Mechanism

2023

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Sterile alpha and toll/interleukin receptor (TIR) motif containing protein 1 (SARM1) is an NAD+ hydrolase and cyclase involved in axonal degeneration. In addition to NAD+ hydrolysis and cyclization, SARM1 catalyzes a base exchange reaction between nicotinic acid (NA) and NADP+ to generate NAADP, which is a potent calcium signaling molecule. Herein, we describe efforts to characterize the hydrolysis, cyclization, and base exchange activities of TIR-1, the Caenorhabditis elegans ortholog of SARM1; TIR-1 also catalyzes NAD(P)+ hydrolysis and/or cyclization and regulates axonal degeneration in worms. We show that the catalytic domain of TIR-1 undergoes a liquid-to-solid phase transition that regulates not only the hydrolysis and cyclization reactions but also the base exchange reaction. We define the substrate specificities of the reactions, demonstrate that cyclization and base exchange reactions occur within the same pH range, and establish that TIR-1 uses a ternary complex mechanism. Overall, our findings will aid drug discovery efforts and provide insight into the mechanism of recently described inhibitors.

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Section: Discussionmentioning

confidence: 77%

Section: ■ Discussionmentioning

confidence: 80%

Section: ■ Discussionmentioning

confidence: 99%

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SARM1, an Enzyme Involved in Axon Degeneration, Catalyzes Multiple Activities through a Ternary Complex Mechanism

2023

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“…In a preclinical model of vincristine‐induced peripheral neuropathy, serum NfL was significantly increased in vincristine‐treated mice at 4 and 6 days after initial injection. Interestingly an inhibitor of sterile alpha and Toll/interleukin‐1 receptor (TIR) motif‐containing 1 (SARM 1) caused a significant reduction in NfL in these vincristine‐treated mice and this corresponded with improvements in mechanical allodynia and IENFD 114 . Furthermore, NfL is a potentially sensitive clinical marker, 111 with studies demonstrating significant elevation in serum prior to the development of CIPN in patients treated with both paclitaxel and carboplatin, highlighting its potential predicative value 113,115 .…”

Section: Pathological Assessment Of Cipn Using Preclinical Modelsmentioning

confidence: 96%

“…Interestingly an inhibitor of sterile alpha and Toll/ interleukin-1 receptor (TIR) motif-containing 1 (SARM 1) caused a significant reduction in NfL in these vincristine-treated mice and this corresponded with improvements in mechanical allodynia and IENFD. 114 Furthermore, NfL is a potentially sensitive clinical marker, 111 with studies demonstrating significant elevation in serum prior to the development of CIPN in patients treated with both paclitaxel and carboplatin, highlighting its potential predicative value. 113,115 NfL is also a good marker of severity with serum levels rising in proportion to the degree of axonal damage (demonstrated by nerve conduction studies) in paclitaxel-treated patients.…”

Section: Pathological Assessments With Preclinical and Clinical Relev...mentioning

confidence: 99%

Targeting translation: A review of preclinical animal models in the development of treatments for chemotherapy‐induced peripheral neuropathy

White

Abdulla

Park

et al. 2023

J Peripheral Nervous Sys

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Background and Aims The expanding use of chemotherapy in curative cancer treatment has simultaneously resulted in a substantial and growing cohort of cancer survivors with prolonged disability from chemotherapy‐induced peripheral neuropathy (CIPN). CIPN is associated with several commonly prescribed chemotherapeutics, including taxanes, platinum‐based drugs, vinca alkaloids, bortezomib and thalidomide. These distinct classes of chemotherapeutics, with their varied neurotoxic mechanisms, often cause patients to suffer from a broad profile of neuropathic symptoms including chronic numbness, paraesthesia, loss of proprioception or vibration sensation and neuropathic pain. Decades of investigation by numerous research groups have provided substantial insights describing this disease. Despite these advances, there is currently no effective curative or preventative treatment option for CIPN and only the dual serotonin–norepinephrine reuptake inhibitor Duloxetine is recommended by clinical guidelines for the symptomatic treatment of painful CIPN. Methods In this review, we examine current preclinical models, with our analysis focused on translational relevance and value. Results Animal models have been pivotal in achieving a better understanding of the pathogenesis of CIPN. However, it has been challenging for researchers to develop appropriate preclinical models that are effective vehicles for the discovery of translatable treatment options. Interpretation Further development of preclinical models targeting translational relevance will promote value for preclinical outcomes in CIPN studies.

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A Covalent Binding Mode of a Pyrazole‐Based CD38 Inhibitor

Bürli

Doyle

Roberts

et al. 2023

Helvetica Chimica Acta

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Brain concentrations of nicotinamide adenine dinucleotide (NAD+), an important cellular co‐factor, tend to decrease with age and in neurodegeneration. As the NADase cluster of differentiation 38 (CD38) significantly contributes to NAD+ consumption, we reasoned that CD38 inhibition may be of therapeutic value for CNS disorders. The new pyrazole compound was designed based on a known CD38 inhibitor and showed good inhibitory potency. Several attempts to co‐crystallise this pyrazole with CD38 and cyclic adenosine diphosphate ribose (cADPR) culminated in a high‐resolution X‐ray structure, in which the pyrazolyl group in the new compound formed a covalent bond with one of the ribosyl units of cADPR. This reaction proceeded under retention of configuration and resulted in a neutral ribosyl‐pyrazole conjugate that is embedded within the active site of the enzyme. An analysis of this structural complex gave rise to design principles that enabled the preparation of more potent CD38 inhibitors with drug‐like properties.

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Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease

Cited by 33 publications

References 62 publications

SARM1, an Enzyme Involved in Axon Degeneration, Catalyzes Multiple Activities through a Ternary Complex Mechanism

SARM1, an Enzyme Involved in Axon Degeneration, Catalyzes Multiple Activities through a Ternary Complex Mechanism

Targeting translation: A review of preclinical animal models in the development of treatments for chemotherapy‐induced peripheral neuropathy

A Covalent Binding Mode of a Pyrazole‐Based CD38 Inhibitor

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