Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine.

نویسندگان

  • Katy N Olafson
  • Megan A Ketchum
  • Jeffrey D Rimer
  • Peter G Vekilov
چکیده

Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-μM concentration of chloroquine fully arrests layer generation and step advancement, which is ∼10(4)× less than hematin's physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials.

برای دانلود 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

An experimental in vitro study to evaluate the antimalarial activity of select homeopathy preparations

Malaria has become the public health concern worldwide. Although it is preventable and curable; P. falciparum and P. vivax have developed resistance to nearly all anti-malarial in current use. New drug discovery and novel drug leads are required to control the current malaria disease burden. The inventor has developed malaria nosode and has subjected it for evaluation of antimalarial activity i...

متن کامل

Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity

The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though ...

متن کامل

Access to hematin: the basis of chloroquine resistance.

The saturable uptake of chloroquine by parasites of Plasmodium falciparum has been attributed to specific carrier-mediated transport of chloroquine. It is suggested that chloroquine is transported in exchange for protons by the parasite membrane Na+/H+ exchanger [J Biol Chem 272:2652-2658 (1997)]. Once inside the parasite, it is proposed that chloroquine inhibits the polymerization of hematin, ...

متن کامل

Antimalarials inhibit hematin crystallization by unique drug-surface site interactions.

In malaria pathophysiology, divergent hypotheses on the inhibition of hematin crystallization posit that drugs act either by the sequestration of soluble hematin or their interaction with crystal surfaces. We use physiologically relevant, time-resolved in situ surface observations and show that quinoline antimalarials inhibit β-hematin crystal surfaces by three distinct modes of action: step pi...

متن کامل

Clinical Pharmacology of the Antimalarial Chloroquine in Children and Their Mothers

Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi are the parasites that infect humans. Plasmodium falciparum and Plasmodium vivax cause most of the malarial infections worldwide. Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi are susceptible to chloroquine. Chloroquine was the world's most widely used antim...

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

برای دانلود 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

عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 112 16  شماره 

صفحات  -

تاریخ انتشار 2015