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Janda currently holds the rank of the Ely R. Callaway, Jr. Chaired Professor in the Departments of Chemistry and Immunology at The Scripps Research Institute (TSRI) in La Jolla, California and is also the Director of the Worm Institute of Research and Medicine (WIRM) at The Scripps Research Institute. Janda holds the title of Professor in the Department of Immunology at The Scripps Research Institute and is a Skaggs Scholar within the Skaggs Institute of Chemical Biology also at The Scripps Research Institute.
Janda has been the recipient of numerous awards including an NIH First Award (1990), Sloan Fellowship (1993) and the Arthur C. Cope Scholar Award (1999).
Additional recommended knowledge
Janda’s career started with his seminal studies on catalytic antibodies. A hallmark of this research was the requirement to blend synthetic organic chemistry with immunology and enzymology – thus working at the interface of chemistry and biology. He has published an impressive body of work on this subject with over ten papers in Science (journal) on research activities in this area. In 1993, his group described for the first time how a catalytic antibody can reroute a chemically disfavored reaction to give an endo Diels-Alder cyclization product rather than the uncatalyzed exo product (Science 259, 490, 1993, doi:10.1126/science.8424171). A second research infusion in this area attributable to Janda was the elucidation of the concept of reactive immunization (Science 270, 1775, 1995, doi:10.1126/science.270.5243.1775). This paper helped to impart new life in the catalytic antibody area that had become stagnant using the transition-state analogue approach.
A second area of research Janda’s group has pioneered is the field of immunopharmacotherapy. This terminology was coined by Janda’s laboratory to describe the use of immune system to target drug addiction and most recently obesity. Janda demonstrated for the first time that one could manipulate the immune system to generate antibodies against one of the most highly addictive drugs known, cocaine (Nature 378, 727, 1995, doi:10.1038/378727a0). This methodology again employs organic synthesis wherein molecules are synthesized to stimulate B-cells to produce antibodies that recognize and effectively remove cocaine before it can crosses the blood brain barrier. He has demonstrated in animal models the exciting potential of such a vaccine and this has led to phase II clinical trials. Furthermore, Janda has demonstrated that antibodies resulting from this approach can protect from the lethal effects of cocaine overdose, even when administered after cocaine exposure (Pharmacol. Biochem. Behav. 81, 709, 2005, doi:10.1016/j.pbb.2005.04.018). Recently, Janda again has provided significant advances in the area of drug addiction with his report detailing the treatment of cocaine addiction with viruses (PNAS 101, 10416, 2004, doi:10.1073/pnas.0403795101). Whereas his previous approach relied on peripheral drug-protein interactions, this approach tackled the problem of delivery of a vaccine directly into the central nervous system and this research opened up unrecognized avenues for addiction treatment. Janda’s laboratory has also expanded this technology to the use of phage-displayed cocaine esterases as potential therapeutics for cocaine addiction (JACS 127, 10016, 2005, doi:10.1021/ja053086a). In a most creative concept, Janda and his colleagues have published what is being hailed by TSRI as their paper of the year a methodology for treating obesity.
Obesity is rapidly becoming “epidemic” in the public health sector, and a great inadequacy of existing obesity treatments. What Janda and colleagues have done (PNAS 103, 13226, 2006, 10.1073/pnas.0605376103 and Commentary 103, 12961, 2006) is present conclusive results demonstrating that an active vaccine against the orexigenic hormone ghrelin can slowed the rate of weight gain, and adiposity, and do this through an entirely metabolic mechanism, as food intake was unchanged. These results were so stunning that media attention has put this on the Today and Tomorrow programs and this work has been Google cited over a million times. This immunopharmacotherapy research has proven general as evidenced by several companies utilizing Janda’s technology in an attempt to treat both cocaine and nicotine addiction and gaining acceptance to both phase I and II clinical trials.
Encoded Combinatorial Libraries
Another area of medicinal research in which the Janda laboratory has made important contributions encompasses techniques to create molecular diversity, uncover active components from complex mixtures and the separation of synthetic targets by phase tagging. Janda has published methodologies that allow implementation of what has been termed “encoded combinatorial libraries” (JACS 115, 9812, 1993, doi:10.1021/ja00074a063 ). The elegance of this work lies in the fact that his group has provided a means whereby the alternating parallel synthesis of peptides and oligonucleotides can be performed in a routine manner. His group has also demonstrated a technology termed “recursive deconvolution of combinatorial libraries” (PNAS 91, 11422, 1994, doi:10.1073/pnas.91.24.11422). The power of this methodology is that any type of chemical or biological screening is applicable, opening up new avenues both in the academic sector as well as industrial efforts. The ability to both conduct practical organic synthesis and also recover the desired product in pure form was eloquently addressed by the Janda group with their publication on liquid phase combinatorial synthesis (PNAS 92, 6419, 1995, doi:10.1073/pnas.92.14.6419). Their initial demonstration that reactants, products and by-products can be effectively “tagged” and targeted to different phases opened up many new research opportunities including the now popular fluorous synthesis.
Over the past 20 years, protein glycation has been implicated in a variety of pathological states. Although smoking also can contribute to many of these disease states, the precise mechanism by which this occurs is unknown. The Janda laboratory demonstrated that nornicotine, a constituent of tobacco, can catalyze aldol reactions in water; this, in fact, is the only known example of a metabolite capable of serving as a catalyst (JACS 124, 3220, 2002, doi:10.1021/ja017774f; JOC 69, 6603, 2004, doi:10.1021/jo048894j). This finding has led him to propose new hypotheses and uncover several previously undescribed chemical links between smoking and metabolic diseases, including that nornicotine causes aberrant protein glycation and thus provides an unrecognized pathway for the development of the pathology of tobacco abuse; additionally nornicotine also catalyzes the covalent modification of certain prescription drugs such as the commonly used steroid, prednisone (PNAS 99, 15084, 2002, doi:10.1073/pnas.222561699). These seminal findings were crucial to his group’s publication on the glycation of the amyloid β-peptide by nornicotine that has further sparked the hypothesis that there is a fortuitous chemical dynamic between smoking and Alzheimer’s disease (PNAS 100, 8182, 2003, doi:10.1073/pnas.1332847100). More recently, Janda’s group has found that nornicotine can also catalyze the isomerization of retinal molecules, possibly implicating nornicotine in the pathology of both age-related macular degeneration as well as smoking-related developmental abnormalities (PNAS 102, 10433, 2005, doi:10.1073/pnas.0504721102). Lastly, his group has linked this glycation process to methamphetamine addiction (JACS 126, 11446, 2004, doi:10.1021/ja047690h). This exciting publication provides the intriguing possibility for an unrecognized mechanism underlying methamphetamine addiction and the pathology of methamphetamine exposure.
Janda’s group has also begun explorations in the area of cell-to-cell communication. In bacteria, the regulation of many important changes in gene expression needed for adaptation to changing environments and competition with multicellular organisms relies on a system of signaling between cells known as “quorum sensing” (QS). Because bacterial genes known to be under quorum sensing regulation are often crucial to their virulence, the study of the compounds that control QS, or autoinducers, may lead to improved antimicrobial pharmaceuticals for the treatment of infectious diseases. During their studies into the development of a program to elicit antibodies against autoinducers, the Janda laboratory has recently discovered that an important class of these molecules, namely the 3-oxo-N-acylhomoserline lactones, performs a previously unrecognized role; the autoinducer itself and corresponding tetramic acid degradation product function as bactericidal agents in a manner analogous to quorum sensing (PNAS 102, 309, 2005, doi:10.1073/pnas.0504721102). Janda’s group also was the first to report a successful chemical synthesis of the autoinducer AI-2, a compound that is employed by both Gram positive and Gram negative bacteria for interspecies communication (Angew. Chem. Int. Ed. 43, 2106, 2004, doi:10.1002/anie.200353150). The completion of the Janda synthesis has allowed the validation of a boronate ester complex of AI-2 as the active signaling species in the symbiotic bacteria V. harveyi.
The Janda laboratory has also made great strides in the development of peptide and antibody molecules for the treatment of cancer. By employing a novel approach based on pVII-pIX phage display for the development of combinatorial phage display peptide libraries, Janda’s group has been able to access and screen a wide range of both sequence space and conformational space (PNAS 96, 6025, 1999, doi:10.1073/pnas.96.11.6025). By panning this library against a B lymphoctye cell line, a unique cell-binding and internalizing peptide was discovered (Bioorg. Med. Chem. 10, 4057, 2002, doi:10.1016/S0968-0896(02)00340-1). Further mechanistic studies of this peptide uncovered both an energy-dependent and energy-independent mechanism for internalization, in essence a dimerization “switch” that modulates the cell-penetrating activity of the peptide (JACS 127, 538, 2005, doi:10.1021/ja0443171). In addition to these studies, Janda has also examined the development of effective immunotherapies for the treatment of cancer. His group has demonstrated that a synthetically prepared cell-surface glycosphingolipid can be utilized as a panning reagent to identify fully human single chain antibodies (scFvs) that are selective for melanoma and breast tumor cells from a combinatorial phage-displayed human antibody library derived from the blood of cancer patients (JACS 124, 12439, 2002, doi:10.1021/ja020737j). The Janda laboratory has also identified a scFv specific for the integrin α3β1 that is internalized by human pancreatic cancer cells (J. Immunol. Methods 274, 185, 2003, doi:10.1016/S0022-1759(02)00522-7); subsequent studies have employed this antibody conjugated with the potent cytotoxic compound duocarmycin SA for the selective delivery of chemotherapeutic agents (Chem. Biol. 11, 897, 2004, doi:10.1016/j.chembiol.2004.04.018).
A final intriguing result in the area of cancer immunotherapy that has been reported by Janda asks the question if the human immune system uses antibodies to innately target tumor cells. To answer this question, combinatorial antibody libraries derived from cancer patients were screened for immunoglobulins that can identify metastatic tumor cells. From these studies, an antibody was identified that is specific for the activated conformation of the adhesion receptor integrin αvβ3 that is associated with a metastatic phenotype (PNAS 101, 17210, 2004, doi:10.1073/pnas.0407869101). Remarkably, two of the identified antibodies possessed the Arg-Gly-Asp integrin recognition motif of the natural ligand. These antibodies interfered with lung colonization by human breast cancer cells in a mouse model and inhibited existing metastatic disease. The implications of this exciting study are that, at some time, these antibodies were part of a patient’s surveillance system against metastatic cells, targeting the activated conformer of integrin αvβ3 and disrupting its functions.
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|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Kim_Janda". A list of authors is available in Wikipedia.|