Loading...

Zoran Radic

TitleAssociate Adjunct Professor
InstitutionUniversity of California San Diego
DepartmentSchool of Pharmacy and Pharmaceutical Science
Address9500 Gilman Drive #0751
La Jolla CA 92093
Phone858-534-6841
vCardDownload vCard

    Collapse Biography 
    Collapse Awards and Honors
    Croatian Society of Natural Sciences2016  - 2017Spiridion Brusina Medal
    New York Academy of Science2016  - 2017Professional Member (by invitation)

    Collapse Overview 
    Collapse Overview
    Dr. Radic is a graduate of the University of Zagreb in Croatia where he started his research in acetylcholinesterase (AChE) reaction kinetics under mentorship of late Dr. Elsa Reiner, one of founding contributors in the field of cholinesterases. His interests in the AChE molecular structure brought him to the laboratory of Dr. Palmer Taylor at UCSD where he provided key contributions to functional mapping of the AChE molecule using site directed mutagenesis and defined structural domains and amino acid residues critical for catalytic activity and ligand interaction. He was the first to propose common, simplified kinetic scheme and equation to describe acetylcholine (ACh) turnover by both AChE and its structurally and functionally close relative butyrylcholinesterase (BChE) that included both substrate inhibition of AChE and substrate activation of BChE, two prominent forms of deviation from Michaelis-Menten kinetcs. Later this scheme and mechanism proved useful for the description of oxime reactivation kinetics of nerve agent organophosphate (OP) and OP pesticide conjugated AChE and BChE including positive allosteric modulation in reactivation of OP-BChE and negative allosteric modulation of OP-AChE conjugates. Dr. Radic developed intrinsic tryptophane fluorescence based assays as a highly valuable tool for in vitro monitoring of time resolved and equilibrium interactions of cholinergic ligands with native nicotinic acetylcholine receptor ligand binding domain surrogates, ACh binding proteins (AChBPs), as well as with AChE and BChE. This assay proved essential in functional characterization of one of tightest known, high affinity binding small molecule femtomolar AChE inhibitors developed in collaboration with Dr. Barry Sharpless of The Scripps Research Institute in La Jolla (TSRI). Dr. Radic leads, as a PI, NIH funded international collaborative project with researchers from TSRI (Dr. Barry K. Sharpless and Dr. Valery Fokin) and Institute for Medical Research and Occupational Health in Zagreb, Croatia (Dr. Zrinka Kovarik) towards development of novel, improved oxime reactivators of OP-AChE and OP-BChE conjugates, both in vitro and in vivo.


    Collapse Research 
    Collapse Research Activities and Funding
    Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
    NIH/NINDS R21NS098998Sep 30, 2016 - Aug 31, 2018
    Role: Principal Investigator
    Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
    NIH/NINDS U01NS083451Jul 15, 2014 - Jun 30, 2019
    Role: Principal Investigator
    BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
    NIH/NINDS R21NS084904Sep 30, 2013 - Aug 31, 2015
    Role: Principal Investigator
    Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
    NIH/NINDS R21NS072086Sep 30, 2010 - Aug 31, 2013
    Role: Principal Investigator

    Collapse ORNG Applications 
    Collapse Featured Presentations
    Collapse Featured Videos

    Collapse Bibliographic 
    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
    List All   |   Timeline
    1. Kovarik Z, Kalisiak J, Hrvat NM, Katalinic M, Zorbaz T, Žunec S, Green C, Radic Z, Fokin VV, Sharpless KB, Taylor P. Reversal of tabun toxicity, enabled by a triazole annulated oxime library-reactivators of acetylcholinesterase. Chemistry. 2018 Nov 20. PMID: 30458057.
      View in: PubMed
    2. Sit RK, Kovarik Z, Macek Hrvat N, Žunec S, Green C, Fokin VV, Sharpless KB, Radic Z, Taylor P. Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure. J Pharmacol Exp Ther. 2018 Nov; 367(2):363-372. PMID: 30190337.
      View in: PubMed
    3. Hagstrom D, Zhang S, Ho A, Tsai ES, Radic Z, Jahromi A, Kaj KJ, He Y, Taylor P, Collins ES. Planarian cholinesterase: molecular and functional characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity. Arch Toxicol. 2018 Mar; 92(3):1161-1176. PMID: 29167930.
      View in: PubMed
    4. Rosenberg YJ, Mao L, Jiang X, Lees J, Zhang L, Radic Z, Taylor P. Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor. Chem Biol Interact. 2017 Aug 25; 274:50-57. PMID: 28693885.
      View in: PubMed
    5. Hagstrom D, Hirokawa H, Zhang L, Radic Z, Taylor P, Collins ES. Planarian cholinesterase: in vitro characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity and reactivation. Arch Toxicol. 2017 Aug; 91(8):2837-2847. PMID: 27990564.
      View in: PubMed
    6. Kovalevsky A, Blumenthal DK, Cheng X, Taylor P, Radic Z. Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning. Ann N Y Acad Sci. 2016 08; 1378(1):41-49. PMID: 27371941.
      View in: PubMed
    7. de Lima WE, Francisco A, da Cunha EF, Radic Z, Taylor P, França TC, Ramalho TC. Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin. J Biomol Struct Dyn. 2017 May; 35(6):1272-1282. PMID: 27125569.
      View in: PubMed
    8. Macek Hrvat N, Žunec S, Taylor P, Radic Z, Kovarik Z. HI-6 assisted catalytic scavenging of VX by acetylcholinesterase choline binding site mutants. Chem Biol Interact. 2016 Nov 25; 259(Pt B):148-153. PMID: 27083141.
      View in: PubMed
    9. Mangas I, Radic Z, Taylor P, Ghassemian M, Candela H, Vilanova E, Estévez J. Butyrylcholinesterase identification in a phenylvalerate esterase-enriched fraction sensitive to low mipafox concentrations in chicken brain. Arch Toxicol. 2017 Feb; 91(2):909-919. PMID: 26838044.
      View in: PubMed
    10. Bourne Y, Sulzenbacher G, Radic Z, Aráoz R, Reynaud M, Benoit E, Zakarian A, Servent D, Molgó J, Taylor P, Marchot P. Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal a7 from Muscle a1(2)ß?d nAChRs. Structure. 2015 Jun 02; 23(6):1106-15. PMID: 26004441; PMCID: PMC4461042.
    11. Kovarik Z, Macek Hrvat N, Katalinic M, Sit RK, Paradyse A, Žunec S, Musilek K, Fokin VV, Taylor P, Radic Z. Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes. Chem Res Toxicol. 2015 May 18; 28(5):1036-44. PMID: 25835984; PMCID: PMC4791098.
    12. Schmidt HR, Radic Z, Taylor P, Fradinger EA. Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system. Toxicol Appl Pharmacol. 2015 Apr 15; 284(2):197-203. PMID: 25701203.
      View in: PubMed
    13. Kaczanowska K, Harel M, Radic Z, Changeux JP, Finn MG, Taylor P. Structural basis for cooperative interactions of substituted 2-aminopyrimidines with the acetylcholine binding protein. Proc Natl Acad Sci U S A. 2014 Jul 22; 111(29):10749-54. PMID: 25006260; PMCID: PMC4115551.
    14. Sit RK, Fokin VV, Amitai G, Sharpless KB, Taylor P, Radic Z. Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification. J Med Chem. 2014 Feb 27; 57(4):1378-89. PMID: 24571195; PMCID: PMC4167068.
    15. Geng L, Gao Y, Chen X, Hou S, Zhan CG, Radic Z, Parks RJ, Russell SJ, Pham L, Brimijoin S. Gene transfer of mutant mouse cholinesterase provides high lifetime expression and reduced cocaine responses with no evident toxicity. PLoS One. 2013; 8(6):e67446. PMID: 23840704; PMCID: PMC3696080.
    16. Morris GM, Green LG, Radic Z, Taylor P, Sharpless KB, Olson AJ, Grynszpan F. Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase. J Chem Inf Model. 2013 Apr 22; 53(4):898-906. PMID: 23451944; PMCID: PMC3698963.
    17. Radic Z, Dale T, Kovarik Z, Berend S, Garcia E, Zhang L, Amitai G, Green C, Radic B, Duggan BM, Ajami D, Rebek J, Taylor P. Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes. Biochem J. 2013 Feb 15; 450(1):231-42. PMID: 23216060; PMCID: PMC4772673.
    18. Kovarik Z, Macek N, Sit RK, Radic Z, Fokin VV, Barry Sharpless K, Taylor P. Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Chem Biol Interact. 2013 Mar 25; 203(1):77-80. PMID: 22960624; PMCID: PMC3530643.
    19. Radic Z, Sit RK, Garcia E, Zhang L, Berend S, Kovarik Z, Amitai G, Fokin VV, Barry Sharpless K, Taylor P. Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates. Chem Biol Interact. 2013 Mar 25; 203(1):67-71. PMID: 22975155; PMCID: PMC3561488.
    20. Radic Z, Sit RK, Kovarik Z, Berend S, Garcia E, Zhang L, Amitai G, Green C, Radic B, Fokin VV, Sharpless KB, Taylor P. Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases. J Biol Chem. 2012 Apr 06; 287(15):11798-809. PMID: 22343626; PMCID: PMC3320928.
    21. Cochran R, Kalisiak J, Küçükkilinç T, Radic Z, Garcia E, Zhang L, Ho KY, Amitai G, Kovarik Z, Fokin VV, Sharpless KB, Taylor P. Oxime-assisted acetylcholinesterase catalytic scavengers of organophosphates that resist aging. J Biol Chem. 2011 Aug 26; 286(34):29718-24. PMID: 21730071; PMCID: PMC3191013.
    22. Valle AM, Radic Z, Rana BK, Mahboubi V, Wessel J, Shih PA, Rao F, O'Connor DT, Taylor P. Naturally occurring variations in the human cholinesterase genes: heritability and association with cardiovascular and metabolic traits. J Pharmacol Exp Ther. 2011 Jul; 338(1):125-33. PMID: 21493754; PMCID: PMC3126649.
    23. Sit RK, Radic Z, Gerardi V, Zhang L, Garcia E, Katalinic M, Amitai G, Kovarik Z, Fokin VV, Sharpless KB, Taylor P. New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases. J Biol Chem. 2011 Jun 03; 286(22):19422-30. PMID: 21464125; PMCID: PMC3103321.
    24. Bourne Y, Radic Z, Taylor P, Marchot P. Conformational remodeling of femtomolar inhibitor-acetylcholinesterase complexes in the crystalline state. J Am Chem Soc. 2010 Dec 29; 132(51):18292-300. PMID: 21090615; PMCID: PMC3016896.
    25. Radic Z, Kalisiak J, Fokin VV, Sharpless KB, Taylor P. Interaction kinetics of oximes with native, phosphylated and aged human acetylcholinesterase. Chem Biol Interact. 2010 Sep 06; 187(1-3):163-6. PMID: 20412789; PMCID: PMC2912944.
    26. Küçükkilinç T, Cochran R, Kalisiak J, Garcia E, Valle A, Amitai G, Radic Z, Taylor P. Investigating the structural influence of surface mutations on acetylcholinesterase inhibition by organophosphorus compounds and oxime reactivation. Chem Biol Interact. 2010 Sep 06; 187(1-3):238-40. PMID: 20382137; PMCID: PMC2933076.
    27. Bourne Y, Radic Z, Aráoz R, Talley TT, Benoit E, Servent D, Taylor P, Molgó J, Marchot P. Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism. Proc Natl Acad Sci U S A. 2010 Mar 30; 107(13):6076-81. PMID: 20224036; PMCID: PMC2851920.
    28. Talley TT, Harel M, Hibbs RE, Radic Z, Tomizawa M, Casida JE, Taylor P. Atomic interactions of neonicotinoid agonists with AChBP: molecular recognition of the distinctive electronegative pharmacophore. Proc Natl Acad Sci U S A. 2008 May 27; 105(21):7606-11. PMID: 18477694; PMCID: PMC2396707.
    29. Radic Z, Manetsch R, Fournier D, Sharpless KB, Taylor P. Probing gorge dimensions of cholinesterases by freeze-frame click chemistry. Chem Biol Interact. 2008 Sep 25; 175(1-3):161-5. PMID: 18555981; PMCID: PMC2585062.
    30. Taylor P, Reiner E, Kovarik Z, Radic Z. Application of recombinant DNA methods for production of cholinesterases as organophosphate antidotes and detectors. Arh Hig Rada Toksikol. 2007 Sep; 58(3):339-45. PMID: 17913689.
      View in: PubMed
    31. Reiner E, Radic Z, Simeon-Rudolf V. Mechanisms of organophosphate toxicity and detoxication with emphasis on studies in Croatia. Arh Hig Rada Toksikol. 2007 Sep; 58(3):329-38. PMID: 17913688.
      View in: PubMed
    32. Cheng Y, Cheng X, Radic Z, McCammon JA. Acetylcholinesterase: mechanisms of covalent inhibition of wild-type and H447I mutant determined by computational analyses. J Am Chem Soc. 2007 May 23; 129(20):6562-70. PMID: 17461584.
      View in: PubMed
    33. Kang TS, Radic Z, Talley TT, Jois SD, Taylor P, Kini RM. Protein folding determinants: structural features determining alternative disulfide pairing in alpha- and chi/lambda-conotoxins. Biochemistry. 2007 Mar 20; 46(11):3338-55. PMID: 17315952; PMCID: PMC4778399.
    34. Cheng Y, Suen JK, Radic Z, Bond SD, Holst MJ, McCammon JA. Continuum simulations of acetylcholine diffusion with reaction-determined boundaries in neuromuscular junction models. Biophys Chem. 2007 May; 127(3):129-39. PMID: 17307283; PMCID: PMC2040065.
    35. Taylor P, Kovarik Z, Reiner E, Radic Z. Acetylcholinesterase: converting a vulnerable target to a template for antidotes and detection of inhibitor exposure. Toxicology. 2007 Apr 20; 233(1-3):70-8. PMID: 17196318; PMCID: PMC3279330.
    36. Hibbs RE, Radic Z, Taylor P, Johnson DA. Influence of agonists and antagonists on the segmental motion of residues near the agonist binding pocket of the acetylcholine-binding protein. J Biol Chem. 2006 Dec 22; 281(51):39708-18. PMID: 17068341.
      View in: PubMed
    37. Kovarik Z, Radic Z, Berman HA, Taylor P. Mutation of acetylcholinesterase to enhance oxime-assisted catalytic turnover of methylphosphonates. Toxicology. 2007 Apr 20; 233(1-3):79-84. PMID: 17046138.
      View in: PubMed
    38. Bourne Y, Radic Z, Sulzenbacher G, Kim E, Taylor P, Marchot P. Substrate and product trafficking through the active center gorge of acetylcholinesterase analyzed by crystallography and equilibrium binding. J Biol Chem. 2006 Sep 29; 281(39):29256-67. PMID: 16837465.
      View in: PubMed
    39. Kovarik Z, Ciban N, Radic Z, Simeon-Rudolf V, Taylor P. Active site mutant acetylcholinesterase interactions with 2-PAM, HI-6, and DDVP. Biochem Biophys Res Commun. 2006 Apr 14; 342(3):973-8. PMID: 16598855.
      View in: PubMed
    40. Bui JM, Radic Z, Taylor P, McCammon JA. Conformational transitions in protein-protein association: binding of fasciculin-2 to acetylcholinesterase. Biophys J. 2006 May 01; 90(9):3280-7. PMID: 16473897; PMCID: PMC1432132.
    41. De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor P. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family. J Biol Chem. 2006 Apr 07; 281(14):9667-76. PMID: 16434405.
      View in: PubMed
    42. Pezzementi L, Shi J, Johnson DA, Radic Z, Boyd A, Taylor P. Ligand-induced conformational changes in residues flanking the active site gorge of acetylcholinesterase. Chem Biol Interact. 2005 Dec 15; 157-158:413-4. PMID: 16429560.
      View in: PubMed
    43. Kovarik Z, Radic Z, Simeon-Rudolf V, Reiner E, Taylor P. Acetylcholinesterase mutants: oxime-assisted catalytic scavengers of organophosphonates. Chem Biol Interact. 2005 Dec 15; 157-158:388-90. PMID: 16429526.
      View in: PubMed
    44. Luo C, Dawson M, Chambers C, Chilukuri N, Radic Z, Taylor P, Doctor BP, Saxena A. Species-related differences in the oxime-induced reactivation of organophosphate-inhibited acetylcholinesterases. Chem Biol Interact. 2005 Dec 15; 157-158:393-4. PMID: 16429528.
      View in: PubMed
    45. Radic Z, Manetsch R, Krasinski A, Raushel J, Yamauchi J, Garcia C, Kolb H, Sharpless KB, Taylor P. Molecular basis of interactions of cholinesterases with tight binding inhibitors. Chem Biol Interact. 2005 Dec 15; 157-158:133-41. PMID: 16289416.
      View in: PubMed
    46. Bourne Y, Radic Z, Kolb HC, Sharpless KB, Taylor P, Marchot P. Structural insights into conformational flexibility at the peripheral site and within the active center gorge of AChE. Chem Biol Interact. 2005 Dec 15; 157-158:159-65. PMID: 16259971.
      View in: PubMed
    47. Krasinski A, Radic Z, Manetsch R, Raushel J, Taylor P, Sharpless KB, Kolb HC. In situ selection of lead compounds by click chemistry: target-guided optimization of acetylcholinesterase inhibitors. J Am Chem Soc. 2005 May 11; 127(18):6686-92. PMID: 15869290.
      View in: PubMed
    48. Zhang D, Suen J, Zhang Y, Song Y, Radic Z, Taylor P, Holst MJ, Bajaj C, Baker NA, McCammon JA. Tetrameric mouse acetylcholinesterase: continuum diffusion rate calculations by solving the steady-state Smoluchowski equation using finite element methods. Biophys J. 2005 Mar; 88(3):1659-65. PMID: 15626705; PMCID: PMC1305222.
    49. Manetsch R, Krasinski A, Radic Z, Raushel J, Taylor P, Sharpless KB, Kolb HC. In situ click chemistry: enzyme inhibitors made to their own specifications. J Am Chem Soc. 2004 Oct 13; 126(40):12809-18. PMID: 15469276.
      View in: PubMed
    50. Taylor P, Hansen SB, Talley TT, Hibbs RE, Radic Z. Contemporary paradigms for cholinergic ligand design guided by biological structure. Bioorg Med Chem Lett. 2004 Apr 19; 14(8):1875-7. PMID: 15050619; PMCID: PMC3191913.
    51. Boyd AE, Dunlop CS, Wong L, Radic Z, Taylor P, Johnson DA. Nanosecond dynamics of acetylcholinesterase near the active center gorge. J Biol Chem. 2004 Jun 18; 279(25):26612-8. PMID: 15078872.
      View in: PubMed
    52. Hansen SB, Talley TT, Radic Z, Taylor P. Structural and ligand recognition characteristics of an acetylcholine-binding protein from Aplysia californica. J Biol Chem. 2004 Jun 04; 279(23):24197-202. PMID: 15069068; PMCID: PMC4762456.
    53. Kovarik Z, Radic Z, Berman HA, Simeon-Rudolf V, Reiner E, Taylor P. Mutant cholinesterases possessing enhanced capacity for reactivation of their phosphonylated conjugates. Biochemistry. 2004 Mar 23; 43(11):3222-9. PMID: 15023072.
      View in: PubMed
    54. Bourne Y, Kolb HC, Radic Z, Sharpless KB, Taylor P, Marchot P. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation. Proc Natl Acad Sci U S A. 2004 Feb 10; 101(6):1449-54. PMID: 14757816; PMCID: PMC341740.
    55. Saxena A, Fedorko JM, Vinayaka CR, Medhekar R, Radic Z, Taylor P, Lockridge O, Doctor BP. Aromatic amino-acid residues at the active and peripheral anionic sites control the binding of E2020 (Aricept) to cholinesterases. Eur J Biochem. 2003 Nov; 270(22):4447-58. PMID: 14622273.
      View in: PubMed
    56. Luo C, Leader H, Radic Z, Maxwell DM, Taylor P, Doctor BP, Saxena A. Two possible orientations of the HI-6 molecule in the reactivation of organophosphate-inhibited acetylcholinesterase. Biochem Pharmacol. 2003 Aug 01; 66(3):387-92. PMID: 12907237.
      View in: PubMed
    57. Kovarik Z, Radic Z, Berman HA, Simeon-Rudolf V, Reiner E, Taylor P. Acetylcholinesterase active centre and gorge conformations analysed by combinatorial mutations and enantiomeric phosphonates. Biochem J. 2003 Jul 01; 373(Pt 1):33-40. PMID: 12665427; PMCID: PMC1223469.
    58. Bourne Y, Taylor P, Radic Z, Marchot P. Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site. EMBO J. 2003 Jan 02; 22(1):1-12. PMID: 12505979; PMCID: PMC140045.
    59. Lewis WG, Green LG, Grynszpan F, Radic Z, Carlier PR, Taylor P, Finn MG, Sharpless KB. Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew Chem Int Ed Engl. 2002 Mar 15; 41(6):1053-7. PMID: 12491310.
      View in: PubMed
    60. Radic Z, Taylor P. Peripheral site ligands accelerate inhibition of acetylcholinesterase by neutral organophosphates. J Appl Toxicol. 2001 Dec; 21 Suppl 1:S13-4. PMID: 11920914.
      View in: PubMed