The aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria.

نویسندگان

  • Tina S Skinner-Adams
  • Christopher L Peatey
  • Karen Anderson
  • Katharine R Trenholme
  • David Krige
  • Christopher L Brown
  • Colin Stack
  • Desire M M Nsangou
  • Rency T Mathews
  • Karine Thivierge
  • John P Dalton
  • Donald L Gardiner
چکیده

Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an ever-increasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.

CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransfo...

متن کامل

Multifactorial mechanisms of resistance to the aminopeptidase inhibitor prodrug CHR 2863 provoke marked sensitization to the mTOR inhibitor rapamycin

Submitted 8 Multifactorial mechanisms of resistance to the aminopeptidase inhibitor prodrug CHR2863 provoke marked sensitization to the mTOR inhibitor rapamycin 176 Abstract Carboxylesterases (CES) play a pivotal role in intracellular metabolic processes of drug detoxification or activation as well as lipid/cholesterol homeosta-sis. Here we report the molecular basis of acquired resistance to C...

متن کامل

A first-in-man phase i and pharmacokinetic study on CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors.

PURPOSE To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro. EXPERIMENTAL DESIGN A phase I study of accelerated titration design that escalated through nine d...

متن کامل

Cancer Therapy: Clinical A First-in-Man Phase I and Pharmacokinetic Study on CHR-2797 (Tosedostat), an Inhibitor of M1 Aminopeptidases, in Patients with Advanced Solid Tumors

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro. Experimental Design: A phase I study of accelerated titration design that escalated through nine d...

متن کامل

Aminopeptidase inhibition as a targeted treatment strategy in myeloma.

Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Antimicrobial agents and chemotherapy

دوره 56 6  شماره 

صفحات  -

تاریخ انتشار 2012