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Lynch, Kevin

Kevin Lynch

Primary Appointment

Pharmacology

Contact Information

PO Box 800735
Charlottesville, VA 22908
Telephone: 434-924-2840
Fax: 434-982-3878
Email: krl2z@virginia.edu

Research Interests

Chemical biology of sphingosine 1-phosphate

Research Description

The over-arching goal of our research is to understand better the biology of sphingosine 1-phosphate (S1P), particularly in the context of disease. S1P is a pleiotropic extracellular lipid that is implicated in control of lymphocyte trafficking, heart rate and vascular leakage. Recently, a S1P receptor agonist pro-drug, fingolimod, was approved as immune system modulator in the treatment of multiple sclerosis. Our central strategy remains the development of tools (mostly small molecules) with which to probe S1P biology. We complement our chemical biology approach with mouse genetics. The new chemical entities that we have developed including S1P receptor agonists and antagonists. The synthesis of these molecules was accomplished in the laboratory of our long term collaborator, Professor Timothy L. Macdonald (Univ. VA Chemistry). The current focus of our work is to develop reagents to explore the mechanisms whereby S1P plasma levels (300 nM) are maintained and consequences of manipulating vascular S1P tone. To this end, we have developed potent inhibitors of the S1P synthetic enzyme, sphingosine kinase (SphK). Administration of our inhibitors to mice and rats revealed that circulating S1P decreased rapidly (minutes) in response to SphK1 inhibition. We have also developed SphK2-selective inhibitors in collaboration with Professor Webster L. Santos (VA Tech Chemistry). Among our current challenges is modifying our SphK inhibitors to make them more persistent in vivo while retaining potency and selectivity. Such molecules will allow testing of the hypothesis that interdicting S1P synthesis at the level of SphK will influence the course of disease in models of inflammation and cancer. Our work is funded by the National Institutes of Health (NIGMS, NICHD), a private foundation and the pharmaceutical industry.

Selected Publications

Cao R, Li J, Kharel Y, Zhang C, Morris E, Santos WL, Lynch KR, Zuo Z, Hu S, Photoacoustic microscopy reveals the hemodynamic basis of sphingosine 1-phosphate-induced neuroprotection against ischemic stroke., 2019; Theranostics. 8(22) 6111-6120 PMID: 30613286 | PMCID: PMC6299683

Adamiak M, Chelvarajan L, Lynch KR, Santos WL, Abdel-Latif A, Ratajczak MZ, Correction: Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells., 2018; Oncotarget. 9(75) 34189 PMID: 30344931 | PMCID: PMC6183342

Kharel Y, Agah S, Huang T, Mendelson AJ, Eletu OT, Barkey-Bircann P, Gesualdi J, Smith JS, Santos WL, Lynch KR, Saccharomyces cerevisiae as a platform for assessing sphingolipid lipid kinase inhibitors., 2018; PloS one. 13(4) e0192179 PMID: 29672528 | PMCID: PMC5908134

Mehaffey JH, Charles EJ, Narahari AK, Schubert S, Laubach VE, Teman NR, Lynch KR, Kron IL, Sharma AK, Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex?vivo lung perfusion., 2018; The Journal of thoracic and cardiovascular surgery. 156(2) 910-917 PMID: 29609890 | PMCID: PMC6056006

Adamiak M, Chelvarajan L, Lynch KR, Santos WL, Abdel-Latif A, Ratajczak MZ, Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells., 2017; Oncotarget. 8(39) 65588-65600 PMID: 29029455 | PMCID: PMC5630355

Childress ES, Kharel Y, Brown AM, Bevan DR, Lynch KR, Santos WL, Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity., 2017; Journal of medicinal chemistry. 60(9) 3933-3957 PMID: 28406646 | PMCID: PMC6047346

Perry HM, Huang L, Ye H, Liu C, Sung SJ, Lynch KR, Rosin DL, Bajwa A, Okusa MD, Endothelial Sphingosine 1?Phosphate Receptor?1 Mediates Protection and Recovery from Acute Kidney Injury., 2016; Journal of the American Society of Nephrology : JASN. 27(11) 3383-3393 PMID: 26961351 | PMCID: PMC5084889

Bajwa A, Huang L, Kurmaeva E, Ye H, Dondeti KR, Chroscicki P, Foley LS, Balogun ZA, Alexander KJ, Park H, Lynch KR, Rosin DL, Okusa MD, Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-?., 2016; Journal of the American Society of Nephrology : JASN. 28(4) 1145-1161 PMID: 27799486 | PMCID: PMC5373443

Lynch KR, Thorpe SB, Santos WL, Sphingosine kinase inhibitors: a review of patent literature (2006-2015)., 2016; Expert opinion on therapeutic patents. 26(12) 1409-1416 PMID: 27539678 | PMCID: PMC5773104

Houck JD, Dawson TK, Kennedy AJ, Kharel Y, Naimon ND, Field SD, Lynch KR, Macdonald TL, Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles., 2016; ACS medicinal chemistry letters. 7(5) 487-92 PMID: 27190598 | PMCID: PMC4867490

Congdon MD, Kharel Y, Brown AM, Lewis SN, Bevan DR, Lynch KR, Santos WL, Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors., 2016; ACS medicinal chemistry letters. 7(3) 229-34 PMID: 26985306 | PMCID: PMC4789682

Congdon MD, Childress ES, Patwardhan NN, Gumkowski J, Morris EA, Kharel Y, Lynch KR, Santos WL, Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors., 2015; Bioorganic & medicinal chemistry letters. 25(21) 4956-4960 PMID: 25862200 | PMCID: PMC4580500

Patwardhan NN, Morris EA, Kharel Y, Raje MR, Gao M, Tomsig JL, Lynch KR, Santos WL, Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors., 2015; Journal of medicinal chemistry. 58(4) 1879-1899 PMID: 25643074 | PMCID: PMC4557804

Nakayama J, Raines TA, Lynch KR, Slack-Davis JK, Decreased peritoneal ovarian cancer growth in mice lacking expression of lipid phosphate phosphohydrolase 1., 2015; PloS one. 10(3) e0120071 PMID: 25769037 | PMCID: PMC4359083

Kharel Y, Morris EA, Congdon MD, Thorpe SB, Tomsig JL, Santos WL, Lynch KR, Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels., 2015; The Journal of pharmacology and experimental therapeutics. 355(1) 23-31 PMID: 26243740 | PMCID: PMC4576667

Bajwa A, Rosin DL, Chroscicki P, Lee S, Dondeti K, Ye H, Kinsey GR, Stevens BK, Jobin K, Kenwood BM, Hoehn KL, Lynch KR, Okusa MD, Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury., 2014; Journal of the American Society of Nephrology : JASN. () PMID: 25145931 |

Taddeo EP, Laker RC, Breen DS, Akhtar YN, Kenwood BM, Liao JA, Zhang M, Fazakerley DJ, Tomsig JL, Harris TE, Keller SR, Chow JD, Lynch KR, Chokki M, Molkentin JD, Turner N, James DE, Yan Z, Hoehn KL, Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle., 2014; Molecular metabolism. 3(2) 124-34 PMID: 24634818 | PMCID: PMC3953683

Santos WL, Lynch KR, Drugging sphingosine kinases., 2014; ACS chemical biology. 10(1) 225-33 PMID: 25384187 | PMCID: PMC4301069

Awojoodu AO, Keegan PM, Lane AR, Zhang Y, Lynch KR, Platt MO, Botchwey EA, Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD., 2014; Blood. 124(12) 1941-50 PMID: 25075126 | PMCID: PMC4168349

Kenwood BM, Weaver JL, Bajwa A, Poon IK, Byrne FL, Murrow BA, Calderone JA, Huang L, Divakaruni AS, Tomsig JL, Okabe K, Lo RH, Cameron Coleman G, Columbus L, Yan Z, Saucerman JJ, Smith JS, Holmes JW, Lynch KR, Ravichandran KS, Uchiyama S, Santos W..., Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane., 2014; Molecular metabolism. 3(2) 114-23 PMID: 24634817 | PMCID: PMC3953706

Kharel Y, Raje M, Gao M, Gellett AM, Tomsig JL, Lynch KR, Santos WL, Sphingosine kinase type?2 inhibition elevates circulating sphingosine 1-phosphate., 2012; The Biochemical journal. 447(1) 149-57 PMID: 22747486 | PMCID: PMC3443596

Bajwa A, Huang L, Ye H, Dondeti K, Song S, Rosin DL, Lynch KR, Lobo PI, Li L, Okusa MD, Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury., 2012; Journal of immunology (Baltimore, Md. : 1950). 189(5) 2584-96 PMID: 22855711 | PMCID: PMC3433235

Gellett AM, Kharel Y, Sunkara M, Morris AJ, Lynch KR, Biosynthesis of alkyl lysophosphatidic acid by diacylglycerol kinases., 2012; Biochemical and biophysical research communications. 422(4) 758-63 PMID: 22627129 | PMCID: PMC3377814

Lynch KR, Building a better sphingosine kinase-1 inhibitor., 2012; The Biochemical journal. 444(1) e1-2 PMID: 22533672 |

Knott K, Kharel Y, Raje MR, Lynch KR, Santos WL, Effect of alkyl chain length on sphingosine kinase 2 selectivity., 2012; Bioorganic & medicinal chemistry letters. 22(22) 6817-20 PMID: 22321213 | PMCID: PMC3394931

East JE, Carter KM, Kennedy PC, Schulte NA, Toews ML, Lynch KR, Macdonald TL, Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist., 2011; MedChemComm. 2(4) 325-330 PMID: 22180836 | PMCID: PMC3237054

Raje MR, Knott K, Kharel Y, Bissel P, Lynch KR, Santos WL, Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors., 2011; Bioorganic & medicinal chemistry. 20(1) 183-94 PMID: 22137932 | PMCID: NIHMS338841

Kharel Y, Mathews TP, Gellett AM, Tomsig JL, Kennedy PC, Moyer ML, Macdonald TL, Lynch KR, Sphingosine kinase type?1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate., 2011; The Biochemical journal. 440(3) 345-53 PMID: 21848514 | PMCID: PMC3443603

Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M, Peyruchaud O, Macdonald TL, Lynch KR, Characterization of a sphingosine 1-phosphate receptor antagonist prodrug., 2011; The Journal of pharmacology and experimental therapeutics. 338(3) 879-89 PMID: 21632869 | PMCID: PMC3164350

Kennedy AJ, Mathews TP, Kharel Y, Field SD, Moyer ML, East JE, Houck JD, Lynch KR, Macdonald TL, Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells., 2011; Journal of medicinal chemistry. 54(10) 3524-48 PMID: 21495716 | PMCID: PMC3119570

Awad AS, Rouse MD, Khutsishvili K, Huang L, Bolton WK, Lynch KR, Okusa MD, Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes., 2011; Kidney international. 79(10) 1090-8 PMID: 21289599 | PMCID: PMC3155206

Kharel Y, Mathews TP, Kennedy AJ, Houck JD, Macdonald TL, Lynch KR, A rapid assay for assessment of sphingosine kinase inhibitors and substrates., 2011; Analytical biochemistry. 411(2) 230-5 PMID: 21216217 | PMCID: PMC3049835

Bajwa A, Jo SK, Ye H, Huang L, Dondeti KR, Rosin DL, Haase VH, Macdonald TL, Lynch KR, Okusa MD, Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury., 2010; Journal of the American Society of Nephrology : JASN. 21(6) 955-65 PMID: 20338995 | PMCID: PMC2900956

Mathews TP, Kennedy AJ, Kharel Y, Kennedy PC, Nicoara O, Sunkara M, Morris AJ, Wamhoff BR, Lynch KR, Macdonald TL, Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors., 2010; Journal of medicinal chemistry. 53(7) 2766-78 PMID: 20205392 | PMCID: PMC2875079

East JE, Kennedy AJ, Tomsig JL, De Leon AR, Lynch KR, Macdonald TL, Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX)., 2010; Bioorganic & medicinal chemistry letters. 20(23) 7132-6 PMID: 20951039 | PMCID: PMC2975792

Okusa MD, Lynch KR, Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury., 2009; Drug discovery today. Disease mechanisms. 4(1) 55-59 PMID: 19448841 | PMCID: PMC2682423

Foss FW, Mathews TP, Kharel Y, Kennedy PC, Snyder AH, Davis MD, Lynch KR, Macdonald TL, Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs., 2009; Bioorganic & medicinal chemistry. 17(16) 6123-36 PMID: 19632123 | PMCID: PMC2793099

Tomsig JL, Snyder AH, Berdyshev EV, Skobeleva A, Mataya C, Natarajan V, Brindley DN, Lynch KR, Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo., 2009; The Biochemical journal. 419(3) 611-8 PMID: 19215222 | PMCID: PMC2677185

Jo SK, Bajwa A, Ye H, Vergis AL, Awad AS, Kharel Y, Lynch KR, Okusa MD, Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury., 2008; Kidney international. 75(2) 167-75 PMID: 18971925 | PMCID: PMC2646633

Lynch KR, Macdonald TL, Sphingosine 1-phosphate chemical biology., 2008; Biochimica et biophysica acta. 1781(9) 508-12 PMID: 18638568 | PMCID: PMC3412363

Wamhoff BR, Lynch KR, Macdonald TL, Owens GK, Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype., 2008; Arteriosclerosis, thrombosis, and vascular biology. 28(8) 1454-61 PMID: 18535287 | PMCID: PMC2605659

Hughes JE, Srinivasan S, Lynch KR, Proia RL, Ferdek P, Hedrick CC, Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages., 2008; Circulation research. 102(8) 950-8 PMID: 18323526 | PMCID: PMC2875063

Jo SK, Bajwa A, Awad AS, Lynch KR, Okusa MD, Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease., 2008; Kidney international. 73(11) 1220-30 PMID: 18322542 | PMCID: PMC2614447

Rivera-Lopez CM, Tucker AL, Lynch KR, Lysophosphatidic acid (LPA) and angiogenesis., 2008; Angiogenesis. 11(3) 301-10 PMID: 18504643 | PMCID: PMC2677190

Cui P, McCalmont WF, Tomsig JL, Lynch KR, Macdonald TL, alpha- and beta-substituted phosphonate analogs of LPA as autotaxin inhibitors., 2007; Bioorganic & medicinal chemistry. 16(5) 2212-25 PMID: 18082408 | PMCID: PMC2907913

Srinivasan S, Bolick DT, Lukashev D, Lappas C, Sitkovsky M, Lynch KR, Hedrick CC, Sphingosine-1-phosphate reduces CD4+ T-cell activation in type 1 diabetes through regulation of hypoxia-inducible factor short isoform I.1 and CD69., 2007; Diabetes. 57(2) 484-93 PMID: 18003758 |

Zhu R, Snyder AH, Kharel Y, Schaffter L, Sun Q, Kennedy PC, Lynch KR, Macdonald TL, Asymmetric synthesis of conformationally constrained fingolimod analogues--discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist., 2007; Journal of medicinal chemistry. 50(25) 6428-35 PMID: 17994678 | PMCID: PMC2895489

Cui P, Tomsig JL, McCalmont WF, Lee S, Becker CJ, Lynch KR, Macdonald TL, Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors., 2007; Bioorganic & medicinal chemistry letters. 17(6) 1634-40 PMID: 17257836 | PMCID: NIHMS20052

Foss FW, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL, Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists., 2006; Bioorganic & medicinal chemistry. 15(2) 663-77 PMID: 17113298 | PMCID: PMC1963459

Awad AS, Ye H, Huang L, Li L, Foss FW, Macdonald TL, Lynch KR, Okusa MD, Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney., 2006; American journal of physiology. Renal physiology. 290(6) F1516-24 PMID: 16403835 |