The University of British Columbia

• Anti-HIV/AIDS drugs
• Kinase inhibitors (CDK's, c-Kit, Aurora and Rho kinases)
• protein-protein interaction inhibitors
• photodynamic therapy
• natural product and novel heterocycle synthesis
• parallel synthesis and small molecule library screenin

A new approach to treating HIV/AIDS  infection: Alternative Splicing Inhibitors

Problems of drug compliance, drug resistance and toxic side effects limit the effectiveness of the combination therapy (HAART) approach to treating HIV/AIDS in the long term. There is thus a constant need for new drugs and in particular those acting through new, and as yet unexplored mechanisms. In collaboration with Pr. Jamal Tazi (U. Montpellier II, France) and Dr. Florence Mahuteau-Betzer (Institut Curie, Orsay, France) we are developing inhibitors of specific alternative splicing events which are vital to the production of the critical HIV proteins Tat, Rev, Vpr, Vpu and Nef.  In particular, Tat plays a key role in virus multiplication, and inhibition of Tat function may provide a means to attack the latent HIV resevoir, thereby irradicating HIV infection. Our lead compound IDC16, identified by small molecule library screening, interfers with the exonic splicing enhancer activity of the splicing factor SF2/ASF, thereby blocking Tat synthesis and assembly of infectious particles. Following on this discovery, we are engaged in the synthesis and development of a new drug for the treatment of HIV/AIDS. This research is novel in that such a drug will target the host cell machinery, rather than a viral proteins which are subject to constant mutation.

Development of Arginine Methyl Transferase inhibitors

Protein Arginine N-Methyltransferases (PRMTs) are eukaryotic enzymes that transfer one or two methyl groups from S-adenosyl-L-methionine (AdoMet) to the terminal nitrogen atoms on arginyl residues within protein substrates, thus producing mono- and/or dimethylarginyl residues and S-adenosyl-L-homocysteine (AdoHcy). This post-translational modification regulates a variety of cellular processes including RNA transcription and processing, and signaling pathways by modulating macromolecular interactions.In collaboration with Professor Adam Frankel (Faculty of Pharmaceutical Sciences) a programme is underway to discover specific inhibitors of PRMT6 using the "fragment" based approach.

Rho-Kinase inhibitors: A strategy for the treatment of diabetic cardiovascular disease

There is mounting evidence to suggest that Rho-Kinase (ROCK) has very important physiological and pathophysiological functions, and in this context isoform selective ROCK inhibitors may have potential as agents to treat diabetic cardiovascular disease.  In collaboration with Prof. Kath MacLeod (Faculty of Pharmaceutical Sciences) a programme has been initiated to design and synthesize a new class of ROCK inhibitors, the ultimate objective being to discover compounds displaying isoform selectivity

HIV/AIDS (Non-Nucleoside Reverse Transcriptase Inhibitors)

• Tosylation/Mesylation of 4-Hydroxy-3-nitro-2-pyridinones as an Activation Step in the Construction of Dihydro[3,4-b] benzo[f][1,4]thiazepin-1-one Based Anti-HIV Agents. P. STORCK, A-M. AUBERTIN, D.S. GRIERSON. Tetrahedron Lett.  46, 2919-2922 (2005)
• 4-Benzyl and 4-Benzoyl-3-dimethylaminopyridin-2(1H)-ones: In vitro Evaluation of New C-3 Amino Substituted and C-5,6 Alkyl Substituted Analogues Against Clinically Important HIV Mutant Strains. A. BENJAHAD, M. CROISY, D. MABIRE, S. COUPA, A. PONCELET, I. CSOKA, J. GUILLEMONT, C. MEYER, K. ANDRIES, R. PAUWELS, M-P. de BETHUNE, C. MONNERET, E. BISAGNI, C.H.NGUYEN, D.S. GRIERSON. J. Med. Chem.(Paul Janssen special edition)  48, 1948-1964 (2005)
• Crystal Structures for HIV1 Reverse transcriptase in Complexes with Three Pyridinone Derivatives : A New Class of Non Nucleoside Inhibitors. D. M. HIMMEL, K. DAS, A.D. CLARK Jr, A. BENJAHAD, S. OMOUCHE, C.H.NGUYEN, J. GUILLEMONT, K. ANDRIES, D.S. GRIERSON, E. ARNOLD. J. Med. Chem. 48, 7582-7591 (2005)
• Structure-Activity Relationship in the 3-Iodo-4-phenoxypyridinone (IOPY) series : The Nature of the C-3 Substituent on Anti HIV Activity. A. BENJAHAD, S. OMOUCHE, J. GUILLEMONT, D. MABIRE, K. ANDRIES, R. PAUWELS, M-P. de BETHUNE, C.H.NGUYEN, D.S. GRIERSON. Biorg. Med. Chem. Lett. 17, 712-716 (2007)

Alternative Splicing Inhibitors (HIV/AIDS, NMD)

• Inhibition of Nonsense-Mediated mRNA Decay (NMD) by a novel chemical molecule reveals the dynamic of NMD factors in P-Bodies. S.DURAND, N.COUGOT, F. MAHUTEAU-BETZER, C-H. NGUYEN, D.S. GRIERSON, E. BERTRAND, J. TAZI, F. LEJEUNE. J. Cell Biol.  178,1145-1160 (2007)
• Small-Molecule Inhibition of HIV pre-m-RNA Splicing as a Novel Antiretroviral Therapy to overcome Drug Resistance. N. BAKKOUR, Y-L. LI, S . MAIRE, L. AYADI, F. MAHUTEAU-BETZER, C-H. NGUYEN, D. GRIERSON, B. CHABOT, P. JEANTUR, P. CORBEAU, C. BRANLANT, J. TAZI. Plos Pathogens 1530 (e159 online) (2007)

DNA Interacting Agents

• Benzoquinoquinoxaline derivatives probe the formation of H-DNA and repress gene expression downstream of the triplex-forming sequence. H. AMIRI, N. NEKHOTIAEVA, J-S SUN, C.H. NGUYEN, D.S. GRIERSON, L. GOOD, R. ZAIN. J. Mol. Biol.  351, 776-783 (2005)
• BENA435, A New Cell-Permiable Photoactivated Green Fluorescent DNA Dye. A. ERVE, Y. SAOUDI, C. GUETTA, S. THIROT, C .H. NGUYEN, D.S. GRIERSON, A.V. POPOV. Nucleic Acids Res. 34, 1900-1911 (2006)

Photodynamic Therapy

• Photodynamic Efficiency of Diethylene Glycol Linked Glycoconjugated Porphyrins in Human Retinoblastoma Cells. I. LAVILLE, S. PIGAGLIO, J-C. BLAIS, B. LOOCK, P. MAILLARD, D.S. GRIERSON, J. BLAIS. J. Med. Chem. 49, 2558-2567 (2006)
• Pharmacokinetics of a Novel Photosensitizer Usable in PDT: The tri Glucoconjugated (Meta)tetrahydroxyphenyl Porphyrin. A Single Dose Study in the Rat. M.C. DESROCHES, A. BAUTISTA_SANCHEZ, C. LAMOTTE, B. LABEQUE, D. AUCHERE, R. FARINOTTI, P. MAILLARD, D.S. GRIERSON, P. PROGNON, A. KASSELOURI. J. Photochem. Photobiol. 85, 56-64 (2006)
• Suzuki Based Coupling Reactions for the  Synthesis of 2-Arylpurines of Biological Interest. L. VANDROMME, L. MEIJER, M. LEGRAVEREND, D.S. GRIERSON. Bioorg Med Chem. Lett. 16, 3144-3146 (2006)
• In vitro phototoxicity of glucosylated porphyrins and chlorins against a retinoblastoma cell line. P. MAILLARD, B. LOOCK, D.S. GRIERSON, I. LAVILLE, J. BLAIS, F. DOZ, L. DESJARDINS, D. CARREZ, J.-L. GUERQUIN, A CROISY. J. Photodiagnostic and Photodynamic Therapy 4, 261-268 (2007)
• Development of Strategies for the Regiocontrolled Synthesis of meso-5,15,20-Triaryl-2,3-chlorins. M. VARAMO, B. LOOCK, P. MAILLARD, D.S. GRIERSON. Organic Letters9, 4689-4692 (2007)

Purine Chemistry and Biology

• Purines as Potent and Versatile Small Molecule Inhibitors of Key Biological Targets. M. LEGRAVEREND, D.S. GRIERSON. Bioorg. Med. Chem.14, 3987-4006 (2006)
• A Pd(0) Cross Coupling Based Approach to the Synthesis of 2-Amidopurines and Their Evaluation as CDK Inhibitors. L. VANDROMME, M. LEGRAVEREND, S. KREIMERMAN, O. LOZACH, L. MEIJER, D.S. GRIERSON. Bioorg Med Chem.15, 131-140 (2007)