Screening And Synthesis Of Isocitrate Lyase Peptide Inhibitor

At present, Tuberculosis(TB) remains to jeopardize human’s health. The emergence of multi-drug-resistant(MDR) and extensively-drug-resistant(XDR) of tuberculosis makes it difficult to cure this disease.The Persistent infeetion of M.tuberculosis and the emergenee of drug-resistant strains Present two major obstaeles in gaining control over tuberculosis worldwide. It is urgent to develop new anti-tubereulosis drugs. Isocitrate lyase (Isocitrate lyase, ICL) is one of the key enzyme of speed of glyoxylate cycle approach, to maintain its n/med tuberculosis bacili withholding was crucial status, so we choose to isocitrate lyase(ICL) as the new anti-tb drug targets.Using the phage peptide library to screen and synthesize peptides for inhibiting ICL activity. Based on three-dimensional crystalline structures of ICL, via the Discovery Studio 2.1 simulate, peptides were docked with ICL protein crystal. The peotides were synthesized by solid-phase synthesis of Fmoc, and their biological activity were detected. Result 6 heptapeptide were gotten by phage peptide library screening and docked with ICL crystal protein successfully. Mass spectrometry detecting showed that they all were correct, molecular weight were 917、746、848、796、658、776. Ultramicro spectrophotometer was used to detect biological activity of the 6 heptapeptides in vitro, and they could inhibit the activity of ICL significantly, theirs inhibition ratio respectively were 75%、64%、66%、 77%、78%、67%, three of theirs were over 70%.Based on crystalline structures of ICL,via Binding Site Analysis of Discovery Studio2.1,the first time found the other large hole in the central part of ICL, it can be combined as new inhibit sites.In this study we optimized the screening of ICL inhibitor, synthesized ICL inhibitor according to the screening result, and provided experiment data for developing new anti-TB drugs.