Isolation, structure, and functional elucidation of a modified pentapeptide, cysteine protease inhibitor (CPI-2081) from Streptomyces species 2081 that exhibit inhibitory effect on cancer cell migration.
Cysteine proteases play an important role in cell migration and tumor metastasis. Therefore, their inhibitors are of colossal interest, having potential to be developed as effective antimetastatic drugs for tumor chemotherapy. Traditionally, secondary metabolites from streptomyces show a wide range of diversity with respect to their biological activity and chemical nature. In this article, we have described the characterization of small molecule cysteine protease inhibitor, CPI-2081 (compound 1), a mixture of two novel pentapeptides, compound 1a (736.71 Da), and compound 1b (842.78 Da), isolated from Streptomyces species NCIM2081, following solvent extraction and repeated HPLC based on C18 chemistry, and completely characterized using a variety of both 1D and 2D NMR spectroscopy. Further, it was found that nanomolar concentration of compound 1 is able to inhibit papain hydrolytic activity. Also, compound 1 significantly inhibits tumor cell migration at sub cytotoxic concentration, indicating its remarkable potential to be developed as antimetastatic drug, which will make chemotherapy more localized and specific, thereby minimizing the hazardous side effects on normal tissues.
Singh
Jay Prakash
JP
Division of Biochemical Sciences, National Chemical Laboratory, Dr. Homi Bhabha Road, Maharastra, Pune 411008, India.
Tamang
Sudarsan
S
Rajamohanan
P R
PR
Jima
N C
NC
Chakraborty
Goutam
G
Kundu
Gopal C
GC
Gaikwad
Sushma M
SM
Khan
Mohamad I
MI
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D010206:Papain / Q000737:chemistry; D011485:Protein Binding; D013302:Streptomyces / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000903:Antibiotics, Antineoplastic; C551615:CPI 2081; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010206:Papain