88
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      KAF156 Is an Antimalarial Clinical Candidate with Potential for Use in Prophylaxis, Treatment, and Prevention of Disease Transmission

      research-article

      a , a , b , c , a , a , a , a , a , a , a , a , a , d ,   d , e , f , f , f , g , h , g , i , i , g , l , j , k , l , m , m , n , k , a , a , a , o , p ,   o , i , f , a , p , a , , q

      Antimicrobial Agents and Chemotherapy

      American Society for Microbiology

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.

          Related collections

          Most cited references 36

          • Record: found
          • Abstract: found
          • Article: not found

          Human malaria parasites in continuous culture.

          Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Drugs for bad bugs: confronting the challenges of antibacterial discovery.

            The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

              Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.
                Bookmark

                Author and article information

                Journal
                Antimicrob Agents Chemother
                Antimicrob. Agents Chemother
                aac
                aac
                AAC
                Antimicrobial Agents and Chemotherapy
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0066-4804
                1098-6596
                September 2014
                September 2014
                : 58
                : 9
                : 5060-5067
                Affiliations
                [a ]Genomics Institute of the Novartis Research Foundation, San Diego, California, USA
                [b ]Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Basel, Switzerland
                [c ]University of Basel, Basel, Switzerland
                [d ]Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA
                [e ]Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
                [f ]Radboud University Nijmegen Medical Center, Medical Microbiology Department, Nijmegen, The Netherlands
                [g ]Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia
                [h ]Eijkman Institute for Molecular Biology, Jakarta, Indonesia
                [i ]Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research, Biopolis, Singapore
                [j ]Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand
                [k ]Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [l ]Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
                [m ]Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
                [n ]Entomology Department, AFRIMS, Bangkok, Thailand
                [o ]Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA
                [p ]Division of Pharmacology and Drug Discovery, University of California, San Diego, School of Medicine, La Jolla, California, USA
                [q ]Novartis Institute for Tropical Diseases, Singapore
                Author notes
                Address correspondence to Thierry T. Diagana, thierry.diagana@ 123456novartis.com .
                [*]

                Present address: Arnab K. Chatterjee, California Institute for Biomedical Research, La Jolla, California, USA.

                Article
                02727-13
                10.1128/AAC.02727-13
                4135840
                24913172
                be862c85-b18b-4217-9a82-76b4937ff47a
                Copyright © 2014 Kuhen et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license.

                Product
                Categories
                Experimental Therapeutics

                Infectious disease & Microbiology

                Comments

                Comment on this article