NOVEL ANTICOAGULANTS FROM HEMATOPHAGOUS ANIMALS

Abstract

THROMBIN AND FACTOR XA PLAY PIVOTAL ROLES IN HAEMOSTASIS, AND THEIR INHIBITORS COMPRISE A SIGNIFICANT FRACTION OF ANTITHROMBOTIC DRUGS. HEMATOPHAGOUS ANIMALS HAVE EVOLVED MOLECULES THAT CONTROL HOST HAEMOSTASIS TO ENSURE A SUCCESSFUL FEEDING. I ADOPTED THREE APPROACHES TO IDENTIFY NOVEL ANTICOAGULANTS: A MICROFLUIDIC CHIP-BASED BIOASSAY COUPLED TO MASS SPECTROMETRY; (2) QUANTITATIVE TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF THE SALIVARY GLAND EXTRACTS OF MALE AND FEMALE DERMACENTOR RETICULATUS; AND SYSTEMATIC ANALYSIS OF EXISTING SEQUENCES. I HAVE IDENTIFIED TWO NOVEL THROMBIN INHIBITORS AND STUDIED THEIR STRUCTURE ACTIVITY RELATIONSHIPS AND DEMONSTRATED ITS IN VIVO EFFICACY IN A MURINE MODEL. I HAVE ALSO DESCRIBED A NEW FAMILY OF THROMBIN INHIBITORS FROM IXODID TICKS, WHICH POSSESS AFFINITIES IN THE NANOMOLAR TO FEMTOMOLAR RANGE, AND SELECTIVELY INHIBIT THROMBIN. I HAVE IDENTIFIED A NOVEL FXA INHIBITOR AND DEVELOPED AN AFFINITY CHROMATOGRAPHY FOR THE PURIFICATION OF THIS FXA INHIBIT