Synthesis of peptide inhibitors for matrix metalloproteinase-2 and angiotensin converting enzyme


Tezin Türü: Yüksek Lisans

Tezin Yürütüldüğü Kurum: Orta Doğu Teknik Üniversitesi, Fen Edebiyat Fakültesi, Kimya Bölümü, Türkiye

Tezin Onay Tarihi: 2014

Öğrenci: BURÇE ÇİFÇİ

Eş Danışman: SALİH ÖZÇUBUKÇU, CAN ÖZEN

Özet:

Matrix Metalloproteinases (MMPs) are one of the enzyme families of proteases that have zinc atom in the active site and they are involved in the degradation and regeneration of extracellular matrix. Specifically, they play an important role in tumor formation, tissue invasion, angiogenesis, and tumor metastasis. Matrix metalloprotease-2 (MMP-2) is a member of gelatinase class of MMP family and it has high activity in progression of skin, prostate, bladder, breast, lung, and ovary cancer. To control this increase in the activity, many MMP inhibitors were developed. However, these inhibitors considered to be not successful due to the specificity problem. On the other hand, chlorotoxin (Cltx), originally isolated from the scorpion venom, is a peptide consisting of 36 amino acids and it shows high stability and selective for inhibition of the MMP-2, due to the cysteine knot motif in its structure. Cyclic-chlorotoxin is known to be more stable than linear chlorotoxin in the plasma, since its proteolytic cleavage is significantly lower due to cyclic structure. Aim of this study is to synthesize cyclic and linear chlorotoxin derivatives, selective and highly potent inhibitors that targets MMP-2 which is an important molecular component in cancer therapy. Consequently, only linear chlorotoxin derivative that has 7 additional amino acids could be synthesized. Result of MMP-2 activity assay performed with this derivative showed no inhibitory effect on the enzyme activity. Angiotensin-converting enzyme (ACE), another enzyme that belongs to zinc metallopeptidase family as MMP-2, is a major component of renin-angiotensin system that controls blood pressure and fluid and electrolyte homeostasis. Its best known function is the in vivo conversion of angiotensin I (Ang I) into the potent vasopressor angiotensin II (Ang II). Therefore, ACE inhibitors have a broad range of application in cardiovascular disease, ranging from mild hypertension to post-myocardial infarction. Kojic acid is used as inhibitor of enzyme tyrosinase to treat melanin hyperpigmentation disorders. This inhibitory effect is due to the ability of kojic acid to chelate copper ion at the active site of the enzyme. Kojic acid shows this chelating property with other metal ions such as zinc, nickel, iron and gold. Since ACE has zinc ion in the active site, kojic acid can chelate with zinc ion for the inhibition of this enzyme. Objective of this study is to synthesize conjugates of kojic acid with various small peptides that are expected to show greater selectivity as an ACE inhibitor. As a result, two derivatives of kojic acid-phenylalanine conjugate were synthesized. However, due to the activity problems of commercial ACE, interactions of these conjugates with the enzyme could not be studied.