Pathogenic bacteria are exquisitely adapted microbes that use sophisticated biochemical strategies and factors to interfere with the normal function of the host cell. Virulence determinants refer to those factors (i.e., bacterial toxins, cell damaging proteins, adhesins etc.), which actively cause damage to the host. The symptoms of many bacterial diseases can be directly attributed to the actions of virulence factors, especially protein toxins, which are among the most deadly natural poisons known. The most potent bacterial toxins act by delivering a cytotoxic enzymatic moiety (A-domain) into host cells through pores created by an accompanying channel-forming domain (B-domain). Examples of toxins that employ the "A-B strategy" of cell intoxication include cholera, botulinum, diphtheria, anthrax and the disease-causing toxins secreted by C.difficile. Since bacterial toxins are often solely responsible for the symptoms of many diseases, blocking their action on mammalian cells represents an attractive approach to potentially treat the symptoms of these devastating bacterial diseases.
Using chemical biology and targeted drug discovery approaches combined with molecular biophysics and structural analysis we seek to identify and validate host & toxin targets and discover small molecule hits for further exploration and development. In addition, owing to the unique ability of these toxins to specifically and efficiently deliver their toxic enzymes into cells, an often insurmountable task for many protein-based drugs, we aim to develop toxin-delivery platforms to shuttle otherwise non-cell penetrant therapeutics into cells.
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| Auger A, Beilhartz GL, Zhu S, Cauchon E, Falgueyret JP, Grobler JA, Ehteshami M, Gotte M, Melnyk RA (2011) Impact of Primer-Induced Conformational Dynamics of HIV-1 Reverse Transcriptase on Polymerase Translocation and Inhibition. J Biol Chem 286:2 9575-83.
Tam J, Henault M, Li L, Wang Z, Partridge AW, and Melnyk RA (2011) An Activity-Based Probe for High Throughput Measurements of Triacylglycerol Lipases. Anal Biochem 414(2): 254-60.
Falgueyret JP, Auger A, Cauchon E, and Melnyk RA (2011) A High-Throughput Continuous Assay for Screening and Characterization of Inhibitors of HIV Reverse Transcriptase DNA Polymerase Activity. J Biomol Screen , 16(5): 518-24.
Melnyk RA, Tam J, Boie Y, Kennedy BP, Percival MD (2009) Renin and prorenin activate pathways implicated in organ damage in human mesangial cells independent of angiotensin II production. Am J Nephrol, 30(3): 232-43.
Juris SJ, Melnyk RA, Bolcome RE 3rd, Chan J, Collier RJ (2007) Crosslinked forms of the isolated N-terminal domain of the lethal factor are potent inhibitors of anthrax toxin. Infect Immun , 75 (10): 5052-58.
Melnyk RA, and Collier RJ (2006) A loop network within the anthrax toxin pore positions the phenylalanine clamp in an active conformation. Proc Natl Acad Sci USA ;103(26): 9802-07.
Melnyk RA, Hewitt, K.M, Lacy, D.B., Lin HC, Gessner C, Woods VL, Collier RJ, (2006) Structural Determinants for the Binding of Anthrax Lethal Factor to Oligomeric Protective Antigen. J Biol Chem , 281(3): 1630-35.
Lacy DB, Lin HC, Melnyk RA, Schueler-Furman O, Reither L, Cunningham K, Baker D, Collier RJ. (2005) A model of anthrax toxin lethal factor bound to protective antigen. Proc Natl Acad Sci USA , 102(45): 16409-14.
*Krantz BA, *Melnyk RA, Zhang S, Juris SJ, Lacy DB, Wu Z, Finkelstein A., Collier RJ. (2005) A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science , 309(5735): 777-81.
*co-first authors
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