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Scientist, Chronic Disease, Ottawa Hospital Research Institute
Principle Investigator, Regional Protein Chemistry Centre and Diseases of Ageing Centre
Assistant Professor, Departments Medicine and Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa
Member, School of Graduate Studies, University of Ottawa
Research Interests:
- Mammalian Subtilase Proprotein Convertases (PCs) and their cellular functions
- Protease Inhibitors - design, synthesis and biochemical applications
- Cell penetrating peptides and their applications in drug delivery
- Peptide Hormones and their proteolytic regulations
- Peptidomimetics, Peptide libraries
- Peptiomics and Proteiomics
- Viral and Bacterial infections and role of host PCs
- Protein aggregation, fibrillogenesis and metalo-peptides in Alzheimer's dementia
- Fertility and role of PC4 activity
- Molecular modeling and protein structure/conformation
Major Research Activities:
The major goal of our Protein and Enzyme Chemistry laboratory is to investigate the molecular mechanisms underlying several major human diseases through development of specific inhibitors and identification of protein substrates of mammalian Proprotein Convertases (PCs) and Subtilisin Kexin Isozyme-1 (SKI-1). 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 tumorigenesis. Thus these enzymes are important targets for their interventions. The inhibitors were designed via a combination of structural and modelling 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.
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 either substrates or inhibitors of PCs, thus suggesting a regulatory role of these enzymes in oral hygiene and bacterial infection.
We revealed that labdane diterpene (Andrographolide) and their derivatives are strong inhibitors of convertases, PC1, Furin and PC7. This is the first example of non-peptide inhibitors of PCs. Our work in vitro indicated that these and other PC-inhibitors provide a new arsenal as antiproteolytic agents in viral and cancer therapy.
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.
Our research led to the development a new -turn turn inducing and biradical generating nonnatural amino acid called "Eda" (Ene diyne amino acid) and incorporated in peptides to generate highly potent inhibitors of furin and SKI-1.
Our group worked on cell penetrating peptides and devised an efficient method for intracellular delivery of inhibitors using them.
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.
Finally the group is studying the role of PC4 enzyme in male fertility through the design of small molecule inhibitors.
Research Grants
1. Role of PC4 in Fertilization: Studies using Small Inhibitors, Canadian Institutes of Health Research (2004 - 2007)
2. Development and synthesis of cell transportable peptide and peptidomimetic inhibitors of Subtilisin-Kexin Isozyme 1, Natural Science and Engineering Research Council of Canada (2002 - 2005)
3. Development of furin and SKI-1 inhibitors. Canadian Institutes of Health Research -HOPE scholarship program (2005 - 2009).
Editorial and other activities
Member, Editorial Board, Peptide and Protein Letters (http://www.bentham.org/ppl/index2.html)
Member, International Panel, Medical Science Monitor (http://www.medscimonit.com/)
Member, International Panel, Science Advisory Board (http://scienceboard.net)
Co-Organizer, The Interface of Chemistry and Biology Symposium at PACIFICHEM-2005
http://www.pacifichem.org/c_symposia/c_symp_288.htm
Most Recent Publications (provided by The Ottawa Hospital Library Database)
Ouardouz M;Coderre E;Basak A;Chen A;Zamponi GW;Hameed S;Rehak R;Yin X;Trapp BD;Stys PK;, (2009 Feb), Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors.[see comment], Annals of Neurology, Vol.65, Issue 2, 151-159 -> view abstract
Mohottalage D;Goto N;Basak A;, (2009), Subtilisin kexin isozyme-1 (SKI-1): production, purification, inhibitor design and biochemical applications, Advances in Experimental Medicine & Biology, Vol.611, 83-84
Basak A;Shervani N;Kolajova M;Cherla S;Basak S;, (2009), Novel reactive site loop derived mini-serpin inhibitors of recombinant proprotein convertase 4, Advances in Experimental Medicine & Biology, Vol.611, 105-106
Palmer H;Basak A;, (2009), Effect of phosphorylation on tau aggregation using model peptides and circular dichroism studies, Advances in Experimental Medicine & Biology, Vol.611, 259-261
Zhao E;Zhang D;Basak A;Trudeau VL;, (2009), New insights into granin-derived peptides: evolution and endocrine roles, General and Comparative Endocrinology, -> view abstract
Chretien M;Seidah NG;Basak A;Mbikay M;, (2008 Oct), Proprotein convertases as therapeutic targets, Expert Opinion on Therapeutic Targets, Vol.12, Issue 10, 1289-1300 -> view abstract
Scamuffa N;Basak A;Lalou C;Wargnier A;Marcinkiewicz J;Siegfried G;Chretien M;Calvo F;Seidah NG;Khatib AM;, (2008 Nov), Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7, Gut, Vol.57, Issue 11, 1573-1582 -> view abstract
Ozden S;Lucas-Hourani M;Ceccaldi PE;Basak A;Valentine M;Benjannet S;Hamelin J;Jacob Y;Mamchaoui K;Mouly V;Despres P;Gessain A;Butler-Browne G;Chretien M;Tangy F;Vidalain PO;Seidah NG;, (2008 Aug 8), Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: impairment of the maturation of the E2 surface glycoprotein, Journal of Biological Chemistry, Vol.283, Issue 32, 21899-21908 -> view abstract
Basak A;Shervani NJ;Mbikay M;Kolajova M;, (2008 Aug), Recombinant proprotein convertase 4 (PC4) from Leishmania tarentolae expression system: purification, biochemical study and inhibitor design, Protein Expression & Purification, Vol.60, Issue 2, 117-126 -> view abstract
Basak S;Hao X;Chen A;Chretien M;Basak A;, (2008), Structural and biochemical investigation of heptad repeat derived peptides of human SARS corona virus (hSARS-CoV) spike protein, Protein & Peptide Letters, Vol.15, Issue 9, 874-886 -> view abstract
Note: This is not a complete list of publications. More publications may be available in The Ottawa Hospital Library database and Pubmed (search by last name and initials).
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