Rapamycin in ischemic stroke: Old drug, new tricks?

J Cereb Blood Flow Metab. 2019 01;39(1):20-35

Authors: Hadley G, Beard DJ, Couch Y, Neuhaus AA, Adriaanse BA, DeLuca GC, Sutherland BA, Buchan AM

Abstract
The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, hampered by the necessity of rapidly imaging patients. A therapy that could extend this window by protecting neurons may improve outcome. Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit. This review highlights the potential use of rapamycin as a multimodal therapy, acting on the blood-brain barrier, cerebral blood flow and inflammation, as well as directly on neurons. There is significant potential in applying this old drug in new ways to improve functional outcomes for patients after stroke.

PMID: 30334673 [PubMed - indexed for MEDLINE]

Repurposing auranofin as an intestinal decolonizing agent for vancomycin-resistant enterococci.

Sci Rep. 2018 05 29;8(1):8353

Authors: AbdelKhalek A, Abutaleb NS, Elmagarmid KA, Seleem MN

Abstract
Multidrug-resistant enterococcal pathogens, especially vancomycin-resistant enterococci (VRE), are among the pathogens that require new antibiotic innovation. The colonization of the gut represents a major pathway by which VRE can cause infection and spread to other patients. In the current study, auranofin (FDA-approved rheumatoid arthritis drug) is evaluated for its potential use as a decolonizing agent for VRE. Auranofin was found to exert potent antimicrobial activity against a wide range of enterococcal clinical isolates with a minimum inhibitory concentration of 1 μg/mL. No resistant mutants could be developed against auranofin over the course of 14 passages. Auranofin was also found to exert potent anti-biofilm activity against VRE. Auranofin was superior to linezolid, the drug of choice for VRE infection treatment, in the in vivo mouse model. Auranofin significantly reduced the VRE burden in feces, cecum, and ileum contents after 8 days of treatment. Accordingly, this study provides valuable evidence that auranofin has significant promise as a novel gastrointestinal decolonizing agent for VRE.

PMID: 29844350 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2019/11/04

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Fluvastatin potentiates anticancer activity of vorinostat in renal cancer cells.

Cancer Sci. 2019 Nov 01;:

Authors: Okubo K, Isono M, Miyai K, Asano T, Sato A

Abstract
Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mammalian target of rapamycin (mTOR) pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study demonstrating the beneficial combined effect of vorinostat and fluvastatin in cancer cells.

PMID: 31675763 [PubMed - as supplied by publisher]

Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies.

Br J Cancer. 2019 Nov 01;:

Authors: Kita Y, Hamada A, Saito R, Teramoto Y, Tanaka R, Takano K, Nakayama K, Murakami K, Matsumoto K, Akamatsu S, Yamasaki T, Inoue T, Tabata Y, Okuno Y, Ogawa O, Kobayashi T

Abstract
BACKGROUND: Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC.
METHODS: We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened.
RESULTS: Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA-platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin.
CONCLUSIONS: The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.

PMID: 31673101 [PubMed - as supplied by publisher]

Imatinib Revives the Therapeutic Potential of Metformin on Ewing Sarcoma by Attenuating Tumor Hypoxic Response and Inhibiting Convergent Signaling Pathways.

Cancer Lett. 2019 Oct 28;:

Authors: Nan X, Wang J, Cheng H, Yin Z, Sheng J, Qiu B, Lau CC, Yustein JT, Zhao H, Wong STC

Abstract
Ewing sarcoma (EwS) is an aggressive pediatric tumor treated with intensive cytotoxic chemotherapies. Overall survival for metastatic or relapsed disease is only 20-30%. Metformin has long been an attractive therapeutic option for EwS, but hypoxia limits its efficacy. Through a systematic integration of drug combination screening, bioinformatics analyses, functional and in vivo studies, and correlation with clinical outcome, we identified another known drug, imatinib that could augment the in vivo anti-tumor capacity of metformin by attenuating tumor hypoxic response. This drug combination regimen widely suppressed multiple dominant mechanisms in EwS genesis, growth, and metastasis, including key EWS-FLI1 downstream targets that converge into the PI3K/AKT/mTOR signaling pathway. In addition, the combination significantly enhanced inhibition on tumor cell proliferation by standard EwS chemotherapy drugs, including cyclophosphamide and ifosfamide. This suggests a potential clinical benefit of the metformin/imatinib combination by allowing the reduction in dose intensity of standard chemotherapy without compromising survival outcome and represents a potential faster track application for EwS patients.

PMID: 31672491 [PubMed - as supplied by publisher]

Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations.

Cancer Lett. 2019 02 01;442:262-270

Authors: Loh AHP, Stewart E, Bradley CL, Chen X, Daryani V, Stewart CF, Calabrese C, Funk A, Miller G, Karlstrom A, Krafcik F, Goshorn DR, Vogel P, Bahrami A, Shelat A, Dyer MA

Abstract
Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.

PMID: 30395907 [PubMed - indexed for MEDLINE]

Prediction of novel inhibitors for Crotalus adamanteus l-amino acid oxidase by repurposing FDA-approved drugs: a virtual screening and molecular dynamics simulation investigation.

Drug Chem Toxicol. 2019 Oct 31;:1-10

Authors: Khedrinia M, Aryapour H, Mianabadi M

Abstract
One of the deadliest enzymes in the snake venom is l-amino acid oxidase (LAAO) which plays an important role in the pathophysiological effects during snake envenomation. Some effects of this enzyme on the human body are apoptosis, platelet aggregation, edema, hemorrhage, and cytotoxicity. Hence, inhibiting the enzyme activity to reduce its degradation effects is of great medical and pharmacological importance. On the other hand, drug repurposing is a process to find the new existing drug for a new medical indication. Since Crotalus adamanteus LAAO has no crystal structure in the protein data bank, first, its 3D structure was constructed by homology modeling using 1REO as the template and then modeled structure was evaluated by several algorithms. We screened the FDA-approved drugs by structure-based virtual screening, molecular dynamics (MD) simulation, and Molecular Mechanics Poisson Boltzmann Surface Area (MM/PBSA) to identify new inhibitors for the snake venom LAAO. Interestingly, docking results revealed that half of the hits belong to the propionic acid derivatives drugs. In addition, MD simulation was performed to assess the interaction profile of the docked protein-hits complexes. Meanwhile, Arg88, Gln112, Lys345, Trp356 form consistent hydrogen bond interactions with Dexketoprofen, Flurbiprofen, Ketoprofen, Morphine, and Citric acid during simulation. According to the results, each of the four compounds can be an appropriate inhibitor of LAAO and since our study was based on drug repurposing could be evaluated in phase II clinical trials.

PMID: 31668098 [PubMed - as supplied by publisher]

Learning condyle repositioning during orthognathic surgery with a surgical navigation system.

Int J Oral Maxillofac Surg. 2019 Jul;48(7):952-956

Authors: Lartizien R, Zaccaria I, Savoldelli C, Noyelles L, Chamorey E, Cracowski JL, Bettega G

Abstract
Condyle repositioning during bilateral sagittal splint osteotomy (BSSO) is a challenging step for the inexperienced surgeon. We aimed to demonstrate the benefit of navigation for learning the condyle repositioning. We treated 100 patients who underwent a BSSO. A trainee performed the condyle repositioning of one side in two phases. In the first one, the trainee positioned without watching the screen of the Orthopilot Navigation system (ONS). In the second one, the trainee could use the ONS to replace the condyle. Heuristic, anatomical and functional scores of each phase were recorded. Heuristic (17% vs. 75%; p<0.0001), anatomical (35% vs. 86%; p<0.0001) and functional (14% vs. 56%; p<0.0001) scores were significantly greater with the ONS. The ONS is a promising and original intraoperative learning tool for the repositioning of the condyle during BSSO.

PMID: 30755359 [PubMed - indexed for MEDLINE]

Influence of the anatomical form of the posterior maxilla on the reliability of superior maxillary repositioning by Le Fort I osteotomy.

Int J Oral Maxillofac Surg. 2019 May;48(5):612-619

Authors: Tomomatsu N, Kurohara K, Nakakuki K, Yoshitake H, Kanemaru T, Yamaguchi S, Yoda T

Abstract
Certain patients with facial deformities require superior repositioning of the maxilla via Le Fort I osteotomy; however, the magnitude of superior repositioning of the maxilla is often less than expected. In this study, the correlation between the accuracy of superior repositioning of the maxilla and the anatomical form of the maxillary posterior region was examined. Seventy-five patients who underwent Le Fort I osteotomy without forward movement of the maxilla but with superior repositioning of the maxilla were included in this study. The bone volume around the descending palatine artery (DPA), the angle of the junction between the pterygoid process and the tuberosity, and the distance between the upper second molar and the pterygoid process were measured via three-dimensional analysis. A significant negative correlation (r=-0.566) was found between the bone volume around the DPA and the ratio of repositioning (actual movement divided by expected movement). It is possible that the superior repositioning of the maxilla expected prior to surgery was not sufficiently attained because of the large volume of bone around the DPA. The results of this study show that in some patients, superior repositioning was not achieved at the expected level because of bone interference attributable to the anatomical form of the maxillary posterior region.

PMID: 30503635 [PubMed - indexed for MEDLINE]

[Dutch Medicines Act also applicable to repurposing].

Ned Tijdschr Geneeskd. 2018 04 30;162:

Authors: van Wijngaarden J

Abstract
In this issue of the Dutch Journal of Medicine (NTvG), Strous and Van den Brink argue that Article 68 of the Dutch Medicines Act should be applied to repurposed drugs in a more liberal manner. Medicines prescribed on-label have been authorised by the relevant regulatory authority and are therefore guaranteed to have been substantiated by the necessary evidence and assessed for a positive benefit-risk balance. Article 68 states that medicines may be prescribed off-label only if they are described in the relevant professional treatment standards or guidelines. The more liberal application of Article 68 would allow the prescription of drugs that have not been adequately assessed for evidence substantiating their efficacy and safety in the field for which they are being prescribed. This is unwarranted, for repurposed drugs and for any other drug.

PMID: 30020570 [PubMed - indexed for MEDLINE]

Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy.

JCI Insight. 2018 06 07;3(11):

Authors: Jiang X, Lu W, Shen X, Wang Q, Lv J, Liu M, Cheng F, Zhao Z, Pang X

Abstract
Lung cancer patients treated with tyrosine kinase inhibitors (TKIs) often develop resistance. More effective and safe therapeutic agents are urgently needed to overcome TKI resistance. Here, we propose a medical genetics-based approach to identify indications for over 1,000 US Food and Drug Administration-approved (FDA-approved) drugs with high accuracy. We identified a potentially novel indication for an approved antidepressant drug, sertraline, for the treatment of non-small cell lung cancer (NSCLC). We found that sertraline inhibits the viability of NSCLC cells and shows a synergy with erlotinib. Specifically, the cotreatment of sertraline and erlotinib effectively promotes autophagic flux in cells, as indicated by LC3-II accumulation and autolysosome formation. Mechanistic studies further reveal that dual treatment of sertraline and erlotinib reciprocally regulates the AMPK/mTOR pathway in NSCLC cells. The blockade of AMPK activation decreases the anticancer efficacy of either sertraline alone or the combination. Efficacy of this combination regimen is decreased by pharmacological inhibition of autophagy or genetic knockdown of ATG5 or Beclin 1. Importantly, our results suggest that sertraline and erlotinib combination suppress tumor growth and prolong mouse survival in an orthotopic NSCLC mouse model (P = 0.0005). In summary, our medical genetics-based approach facilitates discovery of new anticancer indications for FDA-approved drugs for the treatment of NSCLC.

PMID: 29875309 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2019/10/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Loss-of-function mutations in human RGS2 differentially regulate pharmacological reactivity of resistance vasculature.

Mol Pharmacol. 2019 Oct 23;:

Authors: Phan HTN, Jackson WF, Shaw V, Watts SW, Neubig RR

Abstract
Regulator of G protein signaling 2 (RGS2) plays a role in reducing vascular contraction and promoting relaxation due to its GTPase accelerating protein activity toward Gαq. Previously, we identified 4 human loss-of-function (LOF) mutations in RGS2 (Q2L, D40Y, R44H and R188H). This study aimed to investigate whether those RGS2 LOF mutations disrupt the ability of RGS2 to regulate vascular reactivity. Isolated mesenteric arteries (MAs) from RGS2-/- mice showed an elevated contractile response to 5 nM angiotensin II and a loss of acetylcholine (ACh)-mediated vasoconstriction. Reintroduction of a wild-type RGS2-GFP plasmid into RGS2-/- MAs suppressed the vasoconstrictor response to angiotensin II. RGS2 LOF mutants failed to suppress the angiotensin II constriction response compared to RGS2 WT. In contrast, ACh-mediated vasoconstriction was restored by expression of RGS2 WT, D40Y and R44H but not by RGS2 Q2L or R188H. Phosphorylation of RGS2 D40Y and R44H by protein kinase G (PKG) may explain their maintained function to support relaxation in MAs. This is supported by phosphomimetic mutants and suppression of vasorelaxation mediated by RGS2 D40Y by a PKG inhibitor. These results demonstrate that RGS2 attenuates vasoconstriction in MAs and that RGS2 LOF mutations cannot carry out this effect. Among them, the Q2L and R188H mutants supported less relaxation to acetylcholine while relaxation mediated by the D40Y and R44H mutant proteins was equal to that with WT protein. Phosphorylation of RGS2 by PKG appears to contribute to this vasorelaxation. These results provide insights for precision medicine targeting the rare individuals carrying these RGS2 mutations. SIGNIFICANCE STATEMENT: The Regulator of G protein Signaling protein 2 (RGS2) has been implicated in control of blood pressure; rare mutations in the RGS2 gene have been identified in large scale human gene sequencing studies. Four human mutations in RGS2 that cause loss-of-function (LOF) in cell-based assays were examined in isolated mouse arteries for effects on both vasoconstriction and vasodilation. All mutants showed the expected LOF effects in suppressing vasoconstriction. Surprisingly, the D40Y and R44H mutant RGS2 showed normal control of vasodilation. We propose that this is due to rescue of the mislocalization phenotype of these two mutants by NO-mediated/PKG-dependent phosphorylation. These mechanisms may guide drug discovery or drug repurposing effort for hypertension by enhancing RGS2 function.

PMID: 31645376 [PubMed - as supplied by publisher]

Repurposing Thioridazine (TDZ) as an anti-inflammatory agent.

Sci Rep. 2018 08 20;8(1):12471

Authors: Baig MS, Roy A, Saqib U, Rajpoot S, Srivastava M, Naim A, Liu D, Saluja R, Faisal SM, Pan Q, Turkowski K, Darwhekar GN, Savai R

Abstract
Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.

PMID: 30127400 [PubMed - indexed for MEDLINE]

Accurate Drug Repositioning through Non-tissue-Specific Core Signatures from Cancer Transcriptomes.

Cell Rep. 2019 Oct 22;29(4):1055

Authors: Xu C, Ai D, Shi D, Suo S, Chen X, Yan Y, Cao Y, Zhang R, Sun N, Chen W, McDermott J, Zhang S, Zeng Y, Han JJ

PMID: 31644902 [PubMed - in process]

Impact of tricyclic antidepressants, selective serotonin reuptake inhibitors, and other antidepressants on overall survival of patients with advanced lung cancer from 2004 to 2014: University of Cincinnati experience.

J Int Med Res. 2019 Oct 23;:300060519862469

Authors: Abdel Karim NF, Hassan R, Siddiqi NI, Eldessouki I, Gaber O, Rahouma M, Kamel M, Yellu M, Gulati S, Xie C, Magdy M, Pruemer J

PMID: 31640444 [PubMed - as supplied by publisher]

LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent.

Sci Rep. 2018 10 08;8(1):14969

Authors: Han HW, Hahn S, Jeong HY, Jee JH, Nam MO, Kim HK, Lee DH, Lee SY, Choi DK, Yu JH, Min SH, Yoo J

Abstract
Sepsis is one of the most common clinical syndromes that causes death and disability. Although many studies have developed drugs for sepsis treatment, none have decreased the mortality rate. The aim of this study was to identify a novel treatment option for sepsis using the library of integrated network-based cellular signatures (LINCS) L1000 perturbation dataset based on an in vitro and in vivo sepsis model. Sepsis-related microarray studies of early-stage inflammatory processes in patients and innate immune cells were collected from the Gene Expression Omnibus (GEO) data repository and used for candidate drug selection based on the LINCS L1000 perturbation dataset. The anti-inflammatory effects of the selected candidate drugs were analyzed using activated macrophage cell lines. CGP-60474, an inhibitor of cyclin-dependent kinase, was the most potent drug. It alleviated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in activated macrophages by downregulating the NF-κB activity, and it reduced the mortality rate in LPS induced endotoxemia mice. This study shows that CGP-60474 could be a potential therapeutic candidate to attenuate the endotoxemic process. Additionally, the virtual screening strategy using the LINCS L1000 perturbation dataset could be a cost and time effective tool in the early stages of drug development.

PMID: 30297806 [PubMed - indexed for MEDLINE]

Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases.

Geroscience. 2019 Oct 21;:

Authors: Yang J, Peng S, Zhang B, Houten S, Schadt E, Zhu J, Suh Y, Tu Z

Abstract
A key goal of geroscience research is to identify effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by screening compounds in model organisms; whether they will be effective in humans is largely unknown. Here we present a new strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological interventions that may "reverse" the age-associated transcriptional changes occurred in these subnetworks. We applied ANDRU to human adipose gene expression data from the Genotype Tissue Expression (GTEx) project. For the top 31 identified compounds, 19 of them showed at least some evidence supporting their function in improving metabolic traits or lifespan, which include type 2 diabetes drugs such as pioglitazone. As the query aging genes were refined to the ones with more intimate links to diseases, ANDRU identified more meaningful drug hits than the general approach without considering the underlying network structures. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.

PMID: 31637571 [PubMed - as supplied by publisher]

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG.

Dis Model Mech. 2019 Oct 21;:

Authors: Iyer S, Sam FS, DiPrimio N, Preston G, Verheijen J, Murthy K, Parton Z, Tsang H, Lao J, Morava E, Perlstein EO

Abstract
Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation affecting over 1,000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. In order to identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multi-species drug repurposing screen using a first-ever worm model of PMM2-CDG followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 are plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains range from 30% to 400% over baseline depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.

PMID: 31636082 [PubMed - as supplied by publisher]