Guler J.L.,University of Washington |
Guler J.L.,University of Virginia |
Freeman D.L.,University of Washington |
Ahyong V.,Howard Hughes Medical Institute |
And 7 more authors.
Malaria drug resistance contributes to up to a million annual deaths. Judicious deployment of new antimalarials and vaccines could benefit from an understanding of early molecular events that promote the evolution of parasites. Continuous in vitro challenge of Plasmodium falciparum parasites with a novel dihydroorotate dehydrogenase (DHODH) inhibitor reproducibly selected for resistant parasites. Genome-wide analysis of independently-derived resistant clones revealed a two-step strategy to evolutionary success. Some haploid blood-stage parasites first survive antimalarial pressure through fortuitous DNA duplications that always included the DHODH gene. Independently-selected parasites had different sized amplification units but they were always flanked by distant A/T tracks. Higher level amplification and resistance was attained using a second, more efficient and more accurate, mechanism for head-to-tail expansion of the founder unit. This second homology-based process could faithfully tune DNA copy numbers in either direction, always retaining the unique DNA amplification sequence from the original A/T-mediated duplication for that parasite line. Pseudo-polyploidy at relevant genomic loci sets the stage for gaining additional mutations at the locus of interest. Overall, we reveal a population-based genomic strategy for mutagenesis that operates in human stages of P. falciparum to efficiently yield resistance-causing genetic changes at the correct locus in a successful parasite. Importantly, these founding events arise with precision; no other new amplifications are seen in the resistant haploid blood stage parasite. This minimizes the need for meiotic genetic cleansing that can only occur in sexual stage development of the parasite in mosquitoes. © 2013 Guler et al. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 436.88K | Year: 2007
DESCRIPTION (provided by applicant): Obesity affects millions of people in the U.S. and worldwide, and this disease has enormous health and economic consequences for our society. Existing treatments show limited efficacy, can possess troubling side effects, and often require long-term therapy. Discovery of a new treatment for obesity would have a very considerable scientific and commercial value. One approach to pharmacotherapy for appetite suppression is the development of 5-HT2C receptor agonists, which was the focus of our Phase One work. In Phase Two, we propose to optimize and further develop these leads through a Structure-Activity Relationship (SAR) program of synthesis and biological evaluation. From this project we specifically aim to discover one or more indole analogs showing efficacy in our animal model for appetite suppression that is equal to or better than approved medications. Such leads will also display favorable drug-like properties. The long-term goal of this project is to discover a new, improved pharmaceutical agent for treatment of obesity that can be licensed and developed for ultimate market approval. 7. Project Narrative Obesity is a serious health problem in the Unites States, and the existing drugs to help people lose weight are often not effective and have side effects. We are carrying out research to discover and develop a new drug for obesity. If we are successful, doctors will have another option to help obese people with their weight problem.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 130.50K | Year: 2008
DESCRIPTION (provided by applicant): Neuropathic pain is a type of chronic pain state caused by injury or disease to the nervous system. Annual medical spending due to pain has been estimated to be over 100 billion. Currently there are no medications ava ilable to prevent or cure this devastating disease condition. Hence, there is an urgent need to discover effective drugs to treat this chronic pain condition. A promising drug target for neuropathic pain is the cannabinoid CB2 receptor. In phase I of this proposal our focus will be on the optimization of our lead compound to discover one or more CB2 receptor agonists with high receptor affinity and selectivity. In order to distinguish between agonist and antagonist activity, analogs that bind effectively to the CB2 receptor, will be evaluated for their ability to stimulate [35S]GTP?S binding. Our specific goal is to develop one or more lead CB2 agonists that show good activity and efficacy in an animal model for neuropathic pain. If this goal is accomplished in Phase I, we will have a drug candidate for further development in Phase II. The long-term goal of this proposal is to develop a medication for neuropathic pain that is effective and without undesirable side effects.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 279.26K | Year: 2013
DESCRIPTION (provided by applicant): Chronic pain can result from various disease conditions and about 45% of the U. S. population seeks medical help for treatment of pain. Neuropathic pain is a type of chronic pain which is very difficult to treat, and most patients do not get adequate relief. A promising therapeutic drug target for the treatment of inflammation and pain is the cannabinoid CB2 receptor. In Phase I of this proposal our focus will be on the structural optimization of our lead template to develop a high efficacy CB2 selective agonist with pain suppression potential and with no CNS side effects. Established in vivo and in vitro pharmacological assays will be used to identify compounds that: 1) are highly selective for CB2 over CB1 receptors; 2)possess high efficacy and high potency in binding and activating the CB2 receptor; 3) possess high efficacy in reversing allodynia (i.e., nociceptive behavior in response to normally non-noxious stimuli); and 4) lack cannabimimetic side effects in whole animals that are typically indicative of CB1 receptor activation. The long-term objective of this proposal is to develop a novel drug for treatment of chronic pain which is both safe and effective. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE:8. Project Narrative Neuropathic pain is a type of chronic pain which is very difficult to treat since most patients do not get adequate relief with existing medications. The goal of this proposal is to develop CB2 receptor agonists with limited or no CNS side effects for the treatment of chronic pain.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 289.82K | Year: 2013
DESCRIPTION (provided by applicant): Metastasis of aggressive breast cancer is a devastating and ultimately fatal condition. The current first- line agents which are used to treat breast cancer metastasis primarily target tumor growth. These drugs produceonly modest increases in survival in patients with aggressive metastatic cancers and have significant side effects. Currently, there are no available treatment options that can specifically and effectively inhibit tumor invasion and metastasis. Therefore,novel drug strategies are needed to treat this chronic, fatal and incurable condition. Our therapeutic strategy for the treatment of aggressive breast cancer is based on reducing Id-1 expression. Id-1 is a key regulator of the invasive and metastatic potential of breast and additional cancers. In this Phase I proposal our focus will be on the optimization of our lead compound to discover one or more analogs that down-regulate Id-1 expression and consequently inhibit breast cancer cell invasion and metastasis. We will also optimize these compounds so that they display a favorable ADME-Tox profile. The ultimate goal of this proposal is to develop a novel therapeutic approach for the treatment of metastatic human breast cancers by down-regulation of Id-1.PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Metastasis of aggressive breast cancer is a devastating and ultimately fatal condition. Currently there are no available treatment options which can effectively inhibit tumor invasion and metastasis. The goal of this proposal is to develop a non-toxic medication for the treatment and prevention of metastatic breast cancer.