John, Varghese, Ph.D.
  • Professor, PI of Drug Discovery Laboratory, Department of Neurology, UCLA

  • Member, of the Alzheimer's Disease Program in the Mary S. Easton Center for Alzheimer's Disease Research

John, Varghese, Ph.D.

Contact

Drug Discovery Laboratory
UCLA Department of Neurology
3131 Reed, 710 Westwood Plaza,
Los Angeles, CA 90095-1769
Tel: (310) 206-4345
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
Lab website: https://drugdiscovery.neurology.ucla.edu

 

Specialty

Medicinal Chemistry, Drug Discovery, Preclinical candidate Development, Therapeutic candidates for Alzheimer’s disease (AD) and CNS disorders.

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Biography

Dr. John is an accomplished medicinal chemist and leads the Drug Discovery Laboratory in the Department of Neurology at UCLA. Dr. John is a member of the Alzheimer’s Disease Program in the Mary S. Easton Center for Alzheimer’s Disease. Previously Dr. John was with Athena Neurosciences and Elan Pharmaceuticals for ~18 years where he was part of project teams developing drug candidates for CNS disorders. These efforts led to clinical candidates for AD and an approved product for multiple sclerosis. His work at Elan included development of potent inhibitors for BACE and γ-secretase, key enzymes in formation Aβ and amyloid plaques. After his industry tenure, he joined the Buck Institute where he led the Alzheimer’s Drug Discovery Network with Dr. Dale Bredesen, the Founding CEO of the Institute. Dr. John is an inventor on over 100 pending or issued patents on compounds for CNS related targets.

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Current Research

The focus of the AD research in the lab include programs to discover molecules targeting varied mechanisms implicated in the disease that affect both phosphorylation and release of tau (p-tau) along with those that modulate postsynaptic uptake of p-tau that could suppress the spread and progression of the disease. These programs are supported by corporate partners and NIH. They include: (1) discovery of molecules that increase the sAPPα, a preclinical candidate from this class DDL-110, has advanced into clinical development for AD by a corporate partner; (2) discovery of molecules that target and reverse the ApoE4-mediated risk factor in AD; (3) discovery of molecules that target secreted clusterin (sCLU) in AD; (4) discovery of corticotrophin factor (CRF) receptor modulators that reduce p-tau and reverse memory deficits; (5) discovery of molecules that target sorting protein-related receptor with A-type repeats (SORLA); and (6) discovery of mimetics of Humanin (HN) as potential therapeutics for AD. The lab is also developing its microfluidic based synthetic exosome (SE) for delivery of protein, antibody and nucleotide based therapeutics for AD and other CNS disorders including SE-ASM for Niemann Pick disease as part of a corporate collaboration.

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Education

  • Ph.D. Medicinal Chemistry, University of Minnesota
  • Fellow, Dr. Josef Fried Laboratory, University of Chicago
  • Fellow, Dr. Carl Djerassi Laboratory, Stanford University

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Publications (Selected)

    • Zhu C, Bilousova T, Focht S, Jun M, Elias CE, Melnik M, Chandra S, Campagna J, Cohn W, Hatami A, Spilman P, Gylys KH, John V. Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson’s disease model. Mol. Brain 2021;14:70. PMCID: PMC8056538
    • Gabrielyan L, Liang H, Minalyan A, Hatami A, John V, Wang L. Behavioral deficits and brain α-synuclein and phosphorylated Serine-129 α-synuclein in male and female mice overexpressing human α-synuclein. J Alzheimer’s Dis. 2021;79:875-893. PMID: 33361597
    • Bilousova T, Simmons BJ, Knapp RR, Elias CJ, Campagna J, Melnik M, Chandra S, Focht S, Zhu C, Vadivel K, Jagodzinska B, Cohn W, Spilman P, Gylys KH, Garg NK, John V. Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the treatment of Alzheimer's disease. ACS Chem Biol. 2020,15(6):1671-1684.
    • Liu J, Campagna J, John V, Damoiseaux R, Mokhonova E, Becerra D, Meng H, McNally EM, Pyle AD, Kramerova I, Spencer MJ. A small –Molecule approach to restore a slow-oxidative phenotype and defective CaMKIIb signaling in Limb Girdle Muscular Dystrophy. Cell Rep Med. 2020;1(7):100122. PMCID: PMC7659555
    • Shu C, Parfenova L, Mokhonova E, Collado JR, Damoiseaux R, Campagna J, John V, Crosbie RH. High-throughput screening identifies modulators of sarcospan that stabilize muscle cells and exhibit activity in the mouse model of Duchene muscular dystrophy. Skeletal Muscle 2020;10:26. PMCID: PMC7499884
    • Duong AT, Simmons BJ, Alam MP, Campagna J, Garg NK, John V. Synthesis of Fused Indolines by Interrupted Fischer Indolization in a Microfluidic Reactor. Tetrahedron Lett. 2019;60(3):322-326. PMCID: PMC6322698
    • Heinzelman P, Powers DN, Wohlschegel JA, John V. Shotgun Proteomic Profiling of Bloodborne Nanoscale Extracellular Vesicles. Methods Mol Biol. 2019;1897:403-416. PMID: 30539460
    • Campagna J, Spilman P, Jagodzinska B, Bai D, Hatami A, Zhu C, Bilousova T, Jun M, Elias CJ, Pham J, Cole G, LaDu MJ, Jung ME, Bredesen DE, John V. A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model. Sci Rep. 2018;8:17574. PMCID: PMC6279743
    • Campagna J, Vadivel K, Jagodzinska B, Bilousova T, Spilman P, John V. Evaluation of an Allosteric BACE Inhibitor Peptide to Identify Mimetics that Can Interact with the Loop F Region of the Enzyme and Prevent APP Cleavage. J Mol Biol. 2018;430(11):1566-1576. PMID: 29649434
    • Bilousova T, Elias C, Miyoshi E, Alam MP, Zhu C, Campagna J, Vadivel K, Jagodzinska B, Gylys KH, John V. Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2. Biochemical and Biophysical Research Communications 2018;499(4):751-757. PMCID: PMC5956110
    • Alam MP, Bilousova T, Spilman P, Vadivel K, Bai D, Elias CJ, Evseenko D, John V. A Small Molecule Mimetic of the Humanin Peptide as a Candidate for Modulating NMDA-Induced Neurotoxicity. ACS Chemical Neuroscience 2018;9(3):462-468. PMID: 29161500
    • Shkhyan R, Van Handel B, Bogdanov J, Lee S, Yu Y, Scheinberg M, Banks NW, Limfat S, Chernostrik A, Franciozi CE, Alam MP, John V, Wu L, Ferguson GB, Nsair A, Petrigliano FA, Vangsness CT, Vadivel K, Bajaj P, Wang L, Liu NQ, Evseenko D. Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann Rheum Dis. 2018;77(5):760-769. PMID: 29436471
    • Subbiah N, Campagna J, Spilman P, Alam MP, Sharma S, Hokugo A, Nishimura I, John V. Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery. Journal of Drug Delivery 2017;2017:4759839. PMCID: PMC5396447
    • Poksay K, Sheffler D, Spilman P, Campagna J, Jagodzinska B, Descamps O, Gorostiza O, Matalis A, Mullenix M, Bredesen DE, Cosford ND, John V. Screening for small molecule inhibitors of statin-induced APP C-terminal toxic fragment production. Frontiers in Experimental Pharmacology and Drug Discovery 2017;8:46. PMCID: PMC5309220
    • Alam MP, Jagodzinska B, Campagna J, Spilman P, John V. C-O bond Formation in a Microfluidic Reactor: High Yield SNAr Substitution of Heteroaryl Chlorides. Tetrahedron Letters 2016;57(19):2059-2062. PMCID: PMC4852388
    • Spilman P, Corset V, Gorostiza O, Poksay K, Galavan V, Zhang J, Rao R, Peters-Libeu C, Vincelette J, McGeehan A, Dovarak-Ewell M, Beyer J, Campagna J, Bankiewicz K, Mehlen P, John V, Bredesen DE. Netrin-1 interrupts Aβ amplification, increases sAβPPα in vitro and in vivo, and improves cognition in a mouse model of Alzheimer’s disease. J. Alzheimer’s Dis. 2016;52(1):223-242. PMID: 27060954
    • Zhang Q, Du G, John V, Kapahi P, Bredesen DE. Alzheimer’s Model Develops Early ADHD Syndrome. J. Neurol. Neurophysiol. 2015;6(6): 1-6. PMCID: PMC4704098
    • Peters-Libeu C, Campagna J, Mitsumori M, Poksay K, Spilman P, Sabogal A, Bredesen DE, John V. sAPPα is a potent endogenous inhibitor of BACE1. J. Alzheimer’s Dis. 2015;47(3):545-555. PMID: 26401691
    • Zhang Q, Descamps O, Hart MJ, Poksay K, Spilman P, Kane D, Gorostiza O, John V, Bredesen DE. Paradoxical effect of TrkA inhibition in Alzheimer’s Disease. J Alzheimers Disease 2014;40(3):605-617. PMCID: PMC4091737
    • Theendakara V, Patent A, Libeu CP, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, John V, Rao RV, and Bredesen DE. Neuroprotective Sirtuin Ratio Reversed by ApoE4. Proceedings of the Proceedings of the National Academy of Sciences of United States of America 2013;110(45):18303-18308. PMCID: PMC3831497
    • Spilman P, Descamps O, Gorostiza O, Libeu CP, Poksay K, Matalis A, Patent A, Rao R, John V, Bredesen DB. The multi-functional drug Tropisetron binds APP and normalizes cognition in a murine Alzheimer's model. Brain Research 2014;1551:25-44. PMCID: PMC4001856
    • Descamps O, Spilman P, Zhang Q, Libeu CP, Poksay K, Gorostiza O, Campagna J, Jagodzinska B, Bredesen DE, John V. AβPP-Selective BACE Inhibitors (ASBI): Novel Class of Therapeutic Agents for Alzheimer's Disease. J Alzheimer’s Disease 2013 ;37(2):343-355. PMCID: PMC3971881
    • Bredesen DE, John V. Next generation therapeutics for Alzheimer's disease. EMBO Mol Med, 2013 5(6):795-798. PMCID: PMC3779441
    • Ng RA, Sun M, Bowers S, Hom RK, Probst GD, John V, Fang LY, Maillard M, Gailunas A, Brogley L, Neitz RJ, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Adler M, Yao N, Zmolek W, Nakamura D, Quinn KP, Sauer JM, Bova MP, Ruslim L, Artis DR, Yednock TA. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors. Bioorg Med Chem Lett. 2013;23(16):4674-4679. PMID: 23856050
    • Libeu CP, Descamps O, Zhang Q, John V, Bredesen DE. Altering APP proteolysis: Increasing sAPPalpha production by Targeting Dimerisation of APP Ectodomain. PLoS One 2012;7(6):e40027. PMCID: PMC3386930
    • Maccechini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and tau levels: target engagement, tolerability and pharmacokinetics in humans. J. of Neurol., Neurosurg. Psychiatry 2012;83(9):894-902. PMCID: PMC3415310
    • Rao RV, Descamps O, John V, Bredesen DE. Ayurvedic medicinal plants for Alzheimer’s disease: a review. Alzheimer’s Research and Therapy 2012;4(3):22-31. PMCID: PMC3506936
    • Libeu CP, Poksay KS, John V, Bredesen DE. Structural and Functional Alterations in Amyloid-β protein precursor Induced by Amyloid- β Preptides. J. Alzheimer’s Disease 2011;25(3):547-566. NIHMS 585475 PMCID: PMC4001850
    • Descamps O, Zhang Q, John V, Bredesen DE. Induction of the C-terminal Proteolytic Cleavage of APP by Statins. J. Alzheimer’s Disease 2011;25(1):51-57. PMID: 21422530
    • Jin K, Mao XO, Xie L, John V, Greenberg DA. Pharmacological Induction of Neuroglobin Expression. Pharmacology 2011;87:81-84. PMCID: PMC3042117
    • Bredesen DE, John V, Galvan V. Importance of the Caspase Cleavage Site in Amyloid-β Protein Precursor. J Alzheimer’s Disease 2010;22(1):57-63. PMCID: PMC3968071
    • Probst GD, Bowers S, Sealy JM, Stupi B, Dressen D, Jagodzinska BM, Aquino J, Gailunas A, Truong AP, Tso L, Xu YZ, Hom RK, John V, Tung JS, Pleiss MA, Tucker JA, Konradi AW, Sham HL, Jagodzinski J, Toth G, Brecht E, Yao N, Pan H, Lin M, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Gauby S, Zmolek W, Quinn KP, Sauer JM. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Structure-activity relationship of the aryl region. Bioorg Med Chem Lett. 2010;20(20):6034-6039. PMID: 20822903
    • Truong AP, Probst GD, Aquino J, Fang L, Brogley L, Sealy JM, Hom RK, Tucker JA, John V, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Tóth G, Yao N, Brecht E, Pan H, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Zmolek W, Quinn KP, Sauer JM. Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents. Bioorg Med Chem Lett. 2010;20(16):4789-4794. PMID: 20634069
    • Sealy JM, Truong AP, Tso L, Probst GD, Aquino J, Hom RK, Jagodzinska BM, Dressen D, Wone DW, Brogley L, John V, Tung JS, Pleiss MA, Tucker JA, Konradi AW, Dappen MS, Toth G, Pan H, Ruslim L, Miller J, Bova MP, Sinha S, Quinn KP, Sauer JM. Design and Synthesis of cell-potent BACE-1 inhibitors: structure-activity relationship of P1’ substituents. Bioorg. Med. Chem. Lett. 2009;19(22):6386-6391. PMID: 19811916
    • Ellerby, HM, Bredesen, DE, Fujimura, S, and John, V. Hunter-killer peptide (HKP) for targeted therapy. J. Med. Chem. 2008;51(19):5887-5892. PMID: 18828573
    • Maillard M, Hom RK, Benson TE, Moon JB, Mamo S, Bienkowski M, Tomasselli AG, Woods DD, Prince DB, Emmons TL, Tucker JT, Dappen MS, Brogley L, Thorsett ED, Jewett N, Sinha S, John V. Design, Synthesis, and Crystal Structure of Hydroxyethyl Secondary Amine-Based Peptidomimetic Inhibitors of Human beta-Secretase. J. Med. Chem. 2007;50(4):776-781. PMID: 17300163
    • Dovey HF, John V, Anderson, JP, Chen LZ, Andrieu PD, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL, Kholedenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Ni B, Nissen JS, Porter WJ, Potts BD, Reel JK, Stephenson D, Su Y, Shipley LA, Whitesitt CA, Yin T, Audia JE. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in the brain. J. Neurochemistry 2001;76(1):173-181. PMID: 11145990
    • John V. Human beta-secretase (BACE) and BACE inhibitors: A Progress Report. Curr Top Med Chem. 2006;6(6):569-578. PMID: 16712492
    • Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, N. Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature. 1999; 402(6761):537-540. PMID: 10591214

Editor

    • “BACE- A Lead Target for Orchestrated Therapy of Alzheimer’s Disease”, Publisher: Wiley and Sons, 2010.

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