An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.
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ABSTRACT:
SUBMITTER: Shi T
PROVIDER: S-EPMC8610018 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.
| S-EPMC7962815 | biostudies-literature
Project description:AbstractThe voltage-gated sodium channel Nav1.7 is highly expressed in nociceptive afferents and is critically involved in pain signal transmission. Nav1.7 is a genetically validated pain target in humans because loss-of-function mutations cause congenital insensitivity to pain and gain-of-function mutations cause severe pain syndromes. Consequently, pharmacological inhibition has been investigated as an analgesic therapeutic strategy. We describe a small molecule Nav1.7 inhibitor, ST-2530, that is an analog of the naturally occurring sodium channel blocker saxitoxin. When evaluated against human Nav1.7 by patch-clamp electrophysiology using a protocol that favors the resting state, the Kd of ST-2530 was 25 ± 7 nM. ST-2530 exhibited greater than 500-fold selectivity over human voltage-gated sodium channel isoforms Nav1.1-Nav1.6 and Nav1.8. Although ST-2530 had lower affinity against mouse Nav1.7 (Kd = 250 ± 40 nM), potency was sufficient to assess analgesic efficacy in mouse pain models. A 3-mg/kg dose administered subcutaneously was broadly analgesic in acute pain models using noxious thermal, mechanical, and chemical stimuli. ST-2530 also reversed thermal hypersensitivity after a surgical incision on the plantar surface of the hind paw. In the spared nerve injury model of neuropathic pain, ST-2530 transiently reversed mechanical allodynia. These analgesic effects were demonstrated at doses that did not affect locomotion, motor coordination, or olfaction. Collectively, results from this study indicate that pharmacological inhibition of Nav1.7 by a small molecule agent with affinity for the resting state of the channel is sufficient to produce analgesia in a range of preclinical pain models.
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Project description:Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.
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Project description:The 90?kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90?, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90?-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.
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Project description:Development of potent and isoform selective nitric oxide synthase (NOS) inhibitors is challenging because of the structural similarity in the heme active sites. One amino acid difference between NOS isoforms, Asp597 in rat neuronal NOS (nNOS) versus Asn368 in bovine endothelial NOS (eNOS), has been identified as the structural basis for why some dipeptide amide inhibitors bind more tightly to nNOS than to eNOS. We now have found that the same amino acid variation is responsible for substantially different binding modes and affinity for a new class of aminopyridine-based inhibitors.
| S-EPMC5287043 | biostudies-literature
Project description:Efficient and robust single-atom catalysts (SACs) based on cheap and earth-abundant elements are highly desirable for electrochemical reduction of nitrogen to ammonia (NRR) under ambient conditions. Herein, for the first time, a Mn-N-C SAC consisting of isolated manganese atomic sites on ultrathin carbon nanosheets is developed via a template-free folic acid self-assembly strategy. The spontaneous molecular partial dissociation enables a facile fabrication process without being plagued by metal atom aggregation. Thanks to well-exposed atomic Mn active sites anchored on two-dimensional conductive carbon matrix, the catalyst exhibits excellent activity for NRR with high activity and selectivity, achieving a high Faradaic efficiency of 32.02% for ammonia synthesis at - 0.45 V versus reversible hydrogen electrode. Density functional theory calculations unveil the crucial role of atomic Mn sites in promoting N2 adsorption, activation and selective reduction to NH3 by the distal mechanism. This work provides a simple synthesis process for Mn-N-C SAC and a good platform for understanding the structure-activity relationship of atomic Mn sites.
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Project description:In previous studies [Delker, S. L., et al. (2010), J. Am. Chem. Soc. 132, 5437-5442], we determined the crystal structures of neuronal nitric oxide synthase (nNOS) in complex with nNOS-selective chiral pyrrolidine inhibitors, designed to have an aminopyridine group bound over the heme where it can electrostatically interact with the conserved active site Glu residue. However, in addition to the expected binding mode with the (S,S)-cis inhibitors, an unexpected "flipped" orientation was observed for the (R,R)-cis enantiomers. In the flipped mode, the aminopyridine extends out of the active site where it interacts with one heme propionate. This prompted us to design and synthesize symmetric "double-headed" inhibitors with an aminopyridine at each end of a bridging ring structure [Xue, F., Delker, S. L., Li, H., Fang, J., Jamal, J., Martásek, P., Roman, L. J., Poulos, T. L., and Silverman, R. B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. (submitted for publication)]. One aminopyridine should interact with the active site Glu and the other with the heme propionate. Crystal structures of these double-headed aminopyridine inhibitors in complexes with nNOS show unexpected and significant protein and heme conformational changes induced by inhibitor binding that result in removal of the tetrahydrobiopterin (H(4)B) cofactor and creation of a new Zn(2+) site. These changes are due to binding of a second inhibitor molecule that results in the displacement of H(4)B and the placement of the inhibitor pyridine group in position to serve as a Zn(2+) ligand together with Asp, His, and a chloride ion. Binding of the second inhibitor molecule and generation of the Zn(2+) site do not occur in eNOS. Structural requirements for creation of the new Zn(2+) site in nNOS were analyzed in detail. These observations open the way for the potential design of novel inhibitors selective for nNOS.
| S-EPMC3193998 | biostudies-literature
Project description:Abstract The peptide bond is the defining feature of proteins, it co ntrols their structure by enforcing planarity and governs their chemistry by abolishing nucleophili city. This behaviour results from the delocalisation of the lone pair of electrons on the nitrogen atom into the adjacent carbonyl bond. Methylating an amide bond by conventional chemistry usually requires a metal to generate the amide anion. The OphA enzyme methyla tes amide bonds at pH 7 in water using S-adenosyl methionine (SAM) as co-factor. The st ructure of OphA reveals a complex catenane arrangement in which the substrate i s clamped adjacent to SAM. Site directed mutants have identified the key catalytic residue s. A mechanism in which conjugation of the peptide bond is disrupted by van der Waals in teractions between SAM and the amide nitrogen is proposed and tested. The methylation of amides is of particular interest as it greatly enhances the cell permeability of peptides.
2020-03-20 | PXD005934 | Pride
Project description:The effects of KS-505a, a novel microbial metabolite, on the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaM-PDE) were investigated. (1) KS-505a potently inhibited the purified 61 kDa isoenzyme of CaM-PDE from bovine brain and required much higher doses to inhibit the purified 59 kDa isoenzyme of CaM-PDE from bovine heart. The inhibition of both isoenzymes was observed only in the presence of calcium-activated calmodulin (Ca2+/CaM). The IC50 values for the 61 and 59 kDa isoenzymes were 0.17 and 13 microM respectively with 20 microM cAMP as a substrate. (2) Kinetic analysis indicated that the inhibitory mode of KS-505a for the 61 kDa isoenzyme was competitive with respect to Ca2+/CaM; the K1 for KS-505a was 0.089 microM. The inhibition was not competitive with respect to the substrates cAMP or cGMP. (3) KS-505a did not interfere with the interaction between Ca2+/CaM and n-phenyll-naphthylamine, a hydrophobic fluorescent probe, nor was it adsorbed to CaM-conjugated gels in the presence of Ca2+, thereby indicating that KS-505a does not bind to Ca2+/CaM. (4) Trypsin-activated 61 kDa isoenzyme, which lacked the Ca2+/CaM-binding domain, was not inhibited by KS-505a at less than micromolar concentrations. Taken together, these results suggest that KS-505a apparently bound to a site in the Ca2+/CaM-binding domain of the 61 kDa isoenzyme and selectively inhibited Ca2+/CaM-activated 61 kDa isoenzyme activity. (5) In rat hippocampal slices, KS-505a at 10 micronM increased the intracellular cAMP concentration to approximately three times the basal level, whereas in rat striatal slices it had no effect on the cAMP concentration at concentrations of 1.0-10 microM, suggesting that each CaM-PDE isoenzyme functions differentially in these regions. These results demonstrate that KS-505a is a highly potent selective inhibitor both in vitro and in vivo and distinguishes between subfamily members within the CaM-PDE family.
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Project description:Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.
| S-EPMC4353635 | biostudies-literature