Det övergripande målet med min forskning har varit att studera interaktion-erna mellan inhibitorer och de virala proteasinteraktion-erna från Hepatit C virus (HCV) och humant cytomegalovirus (HCMV) med syfte att bidra till utvecklingen av nya mer robusta läkemedel som är mindre känsliga mot resistens och genetisk variation. Olika tekniker har användas för dessa interaktionsstudier som i kombination har gett djup viktig kunskap om funktionen av dessa pro-teas och hur framtidens läkemedel mot dessa kan designas. Genom att mäta proteasets aktivitet i närvaro av inhibitorn kan man bestämma i vilken ut-sträckning inhibitorn hämmar proteaset och kan på så sätt bestämma förhål-landet mellan inhibitorernas strukturer och deras förmåga att blockera
pro-teasets aktivitet. Med denna information kan man således guida optimering-en av nya mer effektiva inhibitor. Med biosoptimering-ensorteknik kan man följa inter-aktionen i realtid och således få information om hur hårt inhibitorn binder (affinitet), hur snabbt den binder till (association) och hur snabbt den släpper från (dissociation) proteaset. Det ger en detaljerad vetskap om interaktionens mekaniska processer, något som är mycket värdefullt vid utvecklingen av nya läkemedel. Med biosensorteknik kan man även på ett effektivt sätt sålla ett stort bibliotek (screening) av många små molekylfragment för att kunna identifiera interaktioner. På detta sätt kan helt nya strukturer identifieras som kan byggas ut och antingen hämma proteaset från dess aktiva säte, eller al-losteriskt.
Acknowledgments
During my years at the department of Chemistry-BMC, I have had the privi-lege to be surrounded by so many nice people that have encouraged, helped and supported me. Without you, this work had been impossible.
First and foremost I would like to thank my supervisor Helena Danielson, for accepting me as a PhD-student. You have been inspiring, challenging and encouraging.
My co-supervisor Micke Widersten, for giving me feedback on my research over the years. Gun Stenberg, for sharing your invaluable knowledge in bio-chemistry with me. Gunnar Johansson, for being a brilliant teacher. Doreen, for reading and giving me valuable comments on this thesis, thank you also for your hospitality and for providing us with delicious homemade cookies and cakes every now and then. Francoise, for all our interesting discussions about pedagogics and teaching.
The medicinal chemists Anja Sandstöm, Eva Åkerblom, Pernilla Örtqvist, Anna-Karin Belfrage, Anna Lampa, Johan Gising and Gunnar Lindeberg for a fruitful cooperation and for interesting discussions about organic chemis-try. Especially I would like to thank Eva for input on this thesis and to Anna-Karin for help with structures.
Bosse, for all the help with my computers.
Present members of the HD group and colleagues at the third floor:
Christian Seeger, sharing office with you this last year has been a true privi-lege. You have introduced me to the magic world of LaTeX, showed me how to make nice images in Pymol and backed up my computer files. You have also been a great ski instructor (although you spent most of the time looking for me in the forest). Without your help, encourage and trust, I don’t think this thesis ever had been finalized. Eldar, you have a crazy (almost as bad as mine) sense of humor and the admirable ability to solve all the prob-lems you encounter, and mine as well, especially those I used to have with the 10-ml pipet. Helena N, for really understanding the phrase “This morn-ing was a little bit chaotic”. Sara Solbak, thanks to your incredible negotia-tion skills, we won the battle against the pipet company.
Erika, for every morning knocking on my door with your sweet sunshine smile and telling me that everything will be ok. You are a great source of energy, a talented teacher and a kick-ass spinning instructor. Marcus, for being a skillful glögg maker. Dirk, for bringing new energy to the lab. Anna T, for being a super organizer and for having kakboden-a life saver during the writing of this thesis. Ylva, for keeping me company late nights at BMC.
Former members of the HD group:
Sofia, we started this journey together and you have been a wonderful friend ever since. Thank you for sharing the NS3 project with me and for all the support over these years. Tony, although there are still german-speaking SPR experts in the lab, it has been disturbingly empty here since you left. Johan W, only a talented engineer knows where the mysterious O-rings should be attached in the celldisruptor, and you proved that you are. Malin, with your endless source of energy and enthusiasm, you are inspiring. Göran, for in-troducing me to the NS3 project. Thomas, for all the help with my research projects during the years. Matthis, with interesting discussions about SPR, the föräldrafikas at daycare got so much more exciting. Ikram, for bringing genotype 3a to the lab all the way from Pakistan and for cooking nice food to us.
Several undergraduate students I’ve had the opportunity to supervise during the years have been a great help. Especially I would like to thank Benjamin for being accurate, curious and extremely efficient and Inga, for all the work with the HCMV project.
All the nice organic and biochemists at the fourth floor:
Sara Norrehed, you are a true talent, a great friend and fabulous party-partner. Soon, there will be confetti rain and balloons all over the place. Jo-hanna J, thank you for helping me organize my life every now and then and for making me aware of every time I forgot my mascara. When this is over, the therapy will be open for you again. Johan V, you are a charming fairy.
Cissi, for (almost) always standing out with my curious questions. åsa . . you are a great lunch spinning partner and I cannot see a panda carton without thinking of you. Emil, for the times you stood in for me at course lab. Nisse, for push-up battles in the BMC gym. Huan, it has been great teaching with you. Christian D, for all the cooking inspiration. Magnus, for doing fikas and lunches a little bit funnier. Rickard, for being a much better chair of the PhD association board than I ever was. Tobias, for support and good advice about thesis writing during lunch spinning.
My fabulous friends outside work:
Saramin and André, our life had been indescribable boring without you.
Sara-Lina, if I was a man I would love to be yours :). Pia, thank you for
being openhearted and sincere. Karin Schannong, with your honesty, humor and intellect you constantly give me new perspectives of life. Jenny, for en-couraging me to start doing my PhD, even though it was a great privilege working with you at GE. Bettan och Johanna, Three for All-All for One. It’s just the way it has always been and will always be.
My family:
Mamma, for your endless love, help and support. You are the best grand-mother the boys ever could imagine.
Pappa, thank you for always believing in me.
Chrisse, for all the support, feedback and good advice. You are inspiring.
My sister Elin, for being caring, loving, and understanding. Nail, Jacob, Sara, Tanja, Henrik, Ida, Ebba, faster Zorica, Gurkan, Ingegerd. My sweet cousin Nina, her boyfriend Georgos and my aunt Evaggelio for coming to Sweden now and then and taking care of us. You are the best super nannies in this world, σ’αγαπώ. Susi, you know I love you, thank you for keeping me alive in your own crazy, hilarious way during the writing of this thesis. Val-entin and Anita, my super parents in law for all the support over the years.
Farmor Carin, when it’s hard I’m thinking of your encouraging words and I get a little bit stronger. I know how much you had wanted to read this thesis because I know how proud you had been. I’m sorry I couldn’t make it in time.
Finally, to whom I dedicate this thesis:
Pavel, since the day I met you I have been amazed by your intelligence, con-fidence and incredible discipline. You always give me new insights and per-spectives of Life. Tack för ditt oändliga stöd och för att du vill dela ditt liv med mig.
David and Viktor, you are the most Precious in this world. Jag älskar er.
Angelica, Uppsala 2014
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