Ajoy Basak, PhD

abasak@ohri.ca
Tel: (613) 798-5555, Ext. 16134 (Office); 16128 (Lab)
Fax: (613) 761-4920

Scientist, Chronic Disease , Ottawa Hospital Research Institute
Principle Investigator, Regional Protein Chemistry Centre
Associate Professor, Departments Medicine and Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa
Member, School of Graduate/Post-Graduate Studies, Faculty of Science, University of Ottawa
Member, Division of Endocrinology

Research Interests:

  1. Mammalian Subtilase Superfamily; The Proprotein Convertases (PCs) or Proprotein Convertase Subtilisin/Kexins (PCSKs) and their function in health and diseases
  2. Proteolytic Enzymes (Proteases) and inhibitors - Design, Synthesis and Biochemical applications
  3. Cell penetrating peptides and their applications in drug delivery
  4. Peptide hormones and their proteolytic regulations
  5. Peptidomimetics, Pseudo-, Enediyno-, Circular and Cyclic peptides, Peptide libraries
  6. Peptiomics and Proteiomics
  7. Viral and bacterial infections and role of host PCSK enzymes
  8. Protein aggregation, Fibrillogenesis and Metalo-peptides in Alzheimer's dementia
  9. Fertility and role of PC4 activity and its inhibitors
  10. Cholesterol regulation by designed PCSK9 inhibitors

Major Research Activities:
(1) The major goal of our Protein and Enzyme Chemistry laboratory is to investigate the molecular mechanisms underlying several major human illnesses such as cancer, hypercholesterolemia and infectious diseases through development of specific inhibitors and identification of protein substrates of mammalian PCSK or PC enzymes including Furin (PCSK3) and and Subtilisin Kexin Isozyme-1 (SKI-1) or PCSK8. These Ca+2-dependent serine proteases are structurally related to bacterial subtilisin and yeast kexin. PCs cleave precursor proteins like growth factors, neuropeptides, surface proteins, hormones, their receptors, viral glycoproteins and bacterial toxins at the carboxy terminal of a basic amino acid comprised of motif Arg/Lys/His-X-X/Lys/Arg-Arg↓. Evidence suggests that these proteases play important roles among others in viral and bacterial infections and tumorgenesis. Thus these enzymes are important targets for their interventions. Inhibitors were designed via a combination of structural and modeling studies of the enzymes as well as solid-phase peptide, peptidomimetic and combinatorial chemistry. Significant progress was achieved towards understanding the functional role of these proteases in terms of their physiological substrates and regulators. Expression and purification of most recombinant PCs and their enzymatic properties were accomplished.

(2) We have conducted extensive studies on the substrate specificity, enzyme kinetics, biological assay, development of antibodies, and design of specific inhibitors of these proteases. Our work has revealed that prodomain polypeptides of PCs/SKI-1 and specific peptide segments derived from them are potent inhibitors of cognate enzymes. We further demonstrated that peptides with carboxy terminal modified with neucleophilic functions such as aldehyde, semicarbazone or oxime represent a new class of inhibitors. We have designed a novel "miniserpin" approach for design of furin inhibitors where by mimicking the the reactive site loop of a large serpin Furthermore, we showed that antibacterial human salivary peptides, Histatin-3/5 are substrates or inhibitors of PCs, suggesting their regulatory role in oral hygiene and bacterial infection.

(3) We revealed that the diterpene, Andrographolide and their derivatives as well as several natural flavonoids of Baicalein type are strong inhibitors of convertases, PC1, Furin, PC4 and/or PC7. These are the initial examples of non-peptide inhibitors of PCs. Our work in vitro indicated that these and other PC-inhibitors provide a new arsenal as anti-proteolytic agents in viral and cancer therapy. Our research led to the development of a new -beta turn inducing and biradical generating nonnatural amino acid called "Eda" (Ene diyne amino acid). Incorporation of EDA in peptides led to new generation of highly potent inhibitors of furin and SKI-1 with in vitro anticancer and antiviral activities.

(4) Using Intramolecularly Quenched Fluorogenic peptides spanning the processing sites of highly virulent Hong Kong, ebola and Respiratory Syncytial viruses, we demonstrated that furin, PC5 and PC7 play major roles in the pathogenesis of these viruses. Very recently, in collaboration with others, we demonstrated that the host convertase furin cleaves spike glycoprotein of human SARS corona virus leading to its fusion with host cell membrane. In recent years our group was involved in the discovery of a yet new subtype of PCs called Subtilisin Kexin Isozyme (SKI-1) that cleave protein substrates at the carboxy terminal of a nonbasic amino acid within the motif Arg-X-Leu/Ile-Leu/Ser/Lys. Our study indicated that SKI-1 is involved in the spread of hemorrhagic fever viruses through its proteyolytic role on their surface proteins. Based on this our group developed in vitro bioassay for SKI-1 activity. Our group has generated a number of SKI-1 inhibitors using "pseudopeptide" approach.

(5) We are also engaged in developing functional inhibitors of PCSK9 as potential regulators of cholesterol clearance by LDL-receptor. Such inhibitors designed from pro and catalytic domains of PCSK9 itself are examined for their cholesterol lowering effects in in vitro and ex vivo conditions.

(6) Our research is also directed towards designing new types of cell penetrating peptides and devised an efficient method for intracellular delivery of inhibitors using them.

(7) The group is also studying hyperphosphorylated tau and amyloid peptides to understand the mechanism of protein aggregation and fibrillogenesis associated with "Alzheimer's and related dementias" and are developing compounds to block protein aggregation.

(8) Finally the group is studying the role of PC4 enzyme in male fertility through the design of small molecule inhibitors. We are also investigating the role of epididymal serpins on PC4 activity and sperm protein processing.

Research Grants
(1) 2011-2013 - Heart & Stroke Foundation of Ontario, “Novel Functional Inhibitors of Proprotein Convertase Subtilisin Kexin 9 (PCSK9) As Cholesterol Regulators”. A. Basak (PI
(2) 2007-2012: CIHR,-Team grant: “Secretory Proteinases in Cardiovascular Disorders”: A. Basak, (co-applicant) + 10 others
(3) 2006-2009: CIHR: "Roles of endocrine proprotein convertases in the small intestine" - A. Basak (Co-applicant) + 5 others
(4) 2008-2012: CIHR-HOPE program - CIHR-Sanofi Aventis Pharma Inc. (Canada-India partnership program) Design, Chemical synthesis and biochemical applications of inhibitors targeting mammalian subtilases. A. Basak (PI
(5) 2008-2009: Ontario Thoracic Society Block grant, Novel Targets for Antiviral Strategy to Treat Severe Acute Respiratory Syndrome (SARS) infection. A. Basak (PI)
(6) 2009-2013: NSERC-Discovery: Synthesis and design of novel peptide and peptidomimetic inhibitors of subtilisin-kexin-isozyme-1 and furin. A. Basak (PI)

Editorial and other memberships

Journals:
* Editorial Board, Protein and Peptide Letters, USA
* Editorial Board, Current Proteomics, USA,
* Editorial Advisory Board, Biochem J, UK,
* Editorial Advisory Board, The Open Enzyme Inhibition Journal, Italy, Bentham
* Editorial Board, Current Chemical Research,  India
* International Panel, Medical Science Monitor, Poland
* Conference Co-Organizer, The Interface of Chemistry and Biology Symposium at PACIFICHEM-2005  http://www.pacifichem.org/c_symposia/c_symp_288.htm
Institutions
* Center for Catalysis Research and Innovation (CCRI), Ottawa
* Ottawa Institute of System Biology (OISB)
* International Consortium on Anti-Virals (ICAV),
* The Science Advisory Board (International panel)

Recent Publications (Listed since 2009, Career total: 121)

2009

  1. M. Ouardouz, E. Coderre, A. Basak, A. Chen, G.W. Zamponi, S. Hameed, R. Rehak, X. Yin, B.D. Trapp and P. K. Stys. Glutamate receptors on myelinated spinal cord axons: GluR6 Kainate Receptors. Annals of Neurology, 65 (2), 151-159. 2009.
  2. H. Palmer and A. Basak. Effect of phosphorylation on tau aggregation using model peptides and circular dichroism studies. Adv Exp Med Biol. 611:259-261, 2009.
  3. A. Basak, N. Shervani, M. Kolajova, S. Cherla, S. Basak. Novel reactive site loop derived mini-serpin inhibitors of recombinant proprotein convertase 4. Adv Exp Med Biol. 611:105-106, 2009.
  4. D. Mohottalage, N. Goto, A. Basak. Subtilisin kexin isozyme-1 (SKI-1): production, purification, inhibitor design and biochemical applications. Adv Exp Med Biol. 611:83-84, 2009.
  5. E. Zhao, A. Basak, A.O. Wong, W. Ko, A. Chen, G.C López, C. L. Grey, L. F. Canosa, G. M. Somoza, J.P. Chang, and V.L. Trudeau. The secretogranin II-derived peptide secretoneurin stimulates luteinizing hormone secretion from gonadotrophs. Endocrinology. 150(5):2273-82, 2009.
  6. E. Zhao, D. Zhang, A. Basak and V.L. Trudeau. New insights into granin-derived peptides: evolution and endocrine roles General and Comparative Endocrinology, 164 (2-3), 161-174, 2009.
  7. Ajoy. Basak, M-A Khatib, D. Mohottalage, S. Basak, M. Kolajova, S.S. Bag and Amit. Basak. A Novel Enediyne Peptide Inhibitor of Furin That Blocks Processing of proPDGF-A, B and proVEGF-C. PLoS One, e7700, 4 (11):1-14, 2009.

2010

  1. C.A. Goubko, S. Majumdar, A. Basak, and X. Cao. Hydrogel cell patterning incorporating photocaged RGDS peptides Biomed Microdevices, 12(3):555-68, 2010 (IF 3.32).
  2. S. Majumdar, B.C. Mohanta, D. Roy Chowdhury, R. Banik, B. Dinda and A. Basak. Proprotein Convertase Inhibitory Activities of Flavonoids Isolated from Oroxylum indicum Curr Med Chem, 17 (19):2049-2058, 2010, (IF 5.27).
  3. A. Basak. A. Chen, N. Scamuffa, D. Mohottalage, S. Basak and A-M. Khatib. Blockade of furin activity and furin-induced tumor cells malignant phenotypes by the chemically synthesized human Furin prodomain. Curr Med Chem, 17 (21): 2214-2221. 2010, (IF 5.27).
  4. H. Palmer-Smith and A. Basak. Regulatory effects of peptides from the pro and catalytic domains of Proprotein Convertase Subtilisin/Kexin 9 on LDL-R. Curr Med Chem, 17 (20):2168-82, 2010, (IF 5.27).
  5. A. Basak, D. Mitra, D. Mohottalage and Ajoy Basak, C2-symmetric Azobenzene-Amino acid Conjugates and Their Inhibitory Properties Against Subtilisin Kexin Isozyme-1. Submitted to Bioorg Med Chem Lett, 20(13), 3977-3981, 2010 (IF 2.5).
  6. E. Zhao, C. Grey, D. Zhang, J. Mennigen, A. Basak, J. Chang, and V.L. Trudeau., Secretoneurin (SN) is a potential paracrine factor from lactotrophs stimulating gonadotropin release in the goldfish pituitary, American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 299, R1290 - 1297, 2010. (IF 3.06).

2011

    • C. Gyamera-Acheampong, F. Sirois, N.J. Denis, P. Mishra, D. Figeys, A. Basak and M. Mbikay. ProPCSK4 is slowly matured to its active form in transfected somatic cells: evidence of interactions with BiP. Molecular and Cellular Biochemistry, 348:43–52, 2011. (IF 1.74)
    • S, Iamsaard, R, Vanichviriyakit, G, Hommalai, A, Saewu, B, Withyachumnarnkul, A, Basak and N, Tanphaichitr, Enzymatic activity of sperm proprotein convertase is important for mammalian fertilization. J Cellular Physiol, Jan 31, doi 10.1002/JCP.22626, [Epub ahead of print], 201, 1, (IF 3.64).
    • S. Majumdar, A. Chen, H. Palmer-Smith and A. Basak. Design, synthesi. Novel Circular, Cyclic and Acyclic Ψ(CH(2)O) Containing Peptide Inhibitors of SKI-1/S1P: Synthesis, Kinetic and Biochemical Evaluations. Curr Med Chem, 18 (18), 2770-2782, 2011 (IF 5.27).
    • E Zhao, J McNeilly, A McNeilly, R Fischer-Colbrie, A Basak, J.Y Seong, and V.L. Trudeau. Secretoneurin Stimulates the Production and Release of Luteinizing Hormone in Mouse LβT2 Gonadotropin Cells. Am J Physiol Endocrinol Metab, 2011 Apr 26. [Epub] PMID: 21521715 (IF 7.05).
    • A. Basak, A. Chen, S. Majumdar and H. Palmer Smith. In vitro assay for protease activity of Proprotein Convertase Subtilisin Kexins (PCSKs): An overall review of existing and new methodologies Proprotein Convertases, Methods in Molecular Biology, Humana Press, (Eds: M. Mbikay and N.G. Seidah), 768, 127-153, 2011 (IF    ).
    • F. Sirois, N. Kaefer, K.A. Currie, M. Chrétien, A. Basak, K.K. Nkongolo and M. Mbikay, The rs6232, rs6234 and rs6235 SNPs at the PCSK1 locus are less frequent in Aboriginal than in Caucasian Canadians: mono-allelic clustering and effects on PC1 biosynthesis. BioMed Central Genetics, (Accepted ), 2011, (IF 2.35).
    • A. Basak, H. Palmer-Smith and P. Mishra, Proprotein Convertase Subtilisin Kexin9 (PCSK9): A Novel Target For Cholesterol Regulation. Prot Pep Let, Special Editorial Board Member issue (Accepted), 2011, (IF 1.76).
    • V.L. Trudeau, A. Basak, W.A. Decatur, H. Hu, C.J. Martyniuk, H Volkoff and E Zhao Is secretoneurin a new hormone? General & Comparative Endocrinology, 50th Anniversary Special Issue, (Submitted, Invited article), 2011. (IF 3.11).

     

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