Division Head and Professor of Chemical Biology & Medicinal Chemistry
William I. Dismukes Fellow in Pharmacy
Welcome to the Fast Lab. We are guided by a broad curiosity about how enzymes work and how we can manipulate their functions. We study the chemistry behind how these proteins accelerate chemical reactions that are important for biological processes and use this information to develop small molecules to regulate the enzyme’s function, to design variant enzymes with altered functions or properties, or to design chemical probes to study the activity of enzymes within living cells. Inhibitors that rely on covalent bond formation as part of their mechanism are of particular interest. We choose to study enzymes that are suitable targets for new drugs, so our work serves as an early step in the development of novel therapeutics. My teaching involves undergraduate students, graduate students, postdoctoral researchers and professional pharmacy students in class and in the laboratory. Our current research projects are in the areas of infectious disease, cancer, and cardiovascular / pulmonary health.
1994 – 1998 Ph.D. Biological Sciences; Northwestern University (Evanston, IL)
Advisor: Richard B. Silverman
Dissertation Title: Inactivation of Nitric Oxide Synthase by
N-Propargylguanidine and N5-(1-Iminoethyl)-L-ornithine
1992 – 1993 Graduate Studies; Biochemistry; Brandeis University (Waltham MA)
Advisor: Lizbeth Hedstrom – Left Program in Good Standing
1988 – 1992 B.S. Chemistry; Wheaton College (Wheaton, IL)
Advisor: D.A. Chignell
2016 – present Division Head, Division of Chemical Biology and Medicinal Chemistry
2016 – present Professor, The University of Texas at Austin
College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
2008 – 2016 Associate Professor (Tenured), The University of Texas at Austin
College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
2002 – 2008 Assistant Professor, The University of Texas at Austin
College of Pharmacy, Division of Medicinal Chemistry
2002 – Present Graduate Studies Committee, Biochemistry, Cell & Molecular Biology, The University of Texas, Austin
Research Tracks: Chemical Biology & Drug Discovery; Biomolecular Structure and Function
1998 – 2002 NIH Postdoctoral Fellow, The Pennsylvania State University (University Park, PA)
Advisor: Stephen J. Benkovic
Grant Title (NIH, F32): Mechanistic Studies of Dinuclear Zinc Metallo-β-lactamase.
Honors and Awards
2015 American Association of Colleges of Pharmacy Academic Research Fellow
2014 Co-Chair, Gordon Research Conference on Enzymes, Co-enzymes and Metabolic Pathways
2013 Co-Vice Chair, Gordon Research Conference on Enzymes, Co-enzymes and Metabolic Pathways
2008 Texas Exes Teaching Award, Pharmacy
2002 – 2004 NIH/NIAID Research Scholar Development Award
2000 – 2002 NIH Postdoctoral Fellowship
April 2020: Kudos to Allie, Pei, Toby and others for their new paper on iminodiacetic acid inhibitors of NDM!
April 2020: Congrats to Alex for winning 1st place poster abstract award for this year’s (virtual) College of Pharmacy Research Excellence Day!
March 2020: Congrats to the Crowder Lab for their launch of MBLinhibitors.com with accompanying paper.
February 2020: Check out our Hornraiser and consider supporting the Virtual Cures Stream for freshman research!
August 2019: Our JBC paper on NDM clinical variants was selected for inclusion in a virtual issue on antibiotics – Great work team!
July 2019: Farewell Alfred! Congrats and best wishes for your new job at Rose-Hulman!
June 2019: Pei’s paper with Rex is out – Congrats! Apparently, serine- and metallo-beta-lactamases have something in common after all.
May 2019: Walt and Alfred catch up w/ colleagues at the 2019 Texas Chemical Biology conference – can you find us?
March 2019: Congrats to Guy for winning an Undergraduate Research Fellowship! (5th in a row for our lab – keep the streak going!)
November 2018: Congrats to Nasa for winning an Undergraduate Research Fellowship!
November 2018: Welcome To Alex! A new postdoctoral scholar from the Vederas lab. Our recruitment lunch must have worked!
September 2018: Congrats to Valerie on successful completion of her M.S. defense for Univ. Bordeaux & Mohammed V Univ.!
August 2018: Alfred’s covalent inhibitor review hits 1000+ Article Views in ~ 4 months – Way to Go!
August 2018: Our NDM evolution paper was chosen as a J. Biol. Chem. Editors’ Pick – Top annual 2% for significance and importance – Check out Pei’s bio!
July 2018: Our paper on the evolution of NDM was recommended by F1000Prime as being of special significance in its field.
July 2018: Our paper on dissecting a covalent inhibitor gets published – Kudos Gayle, Joyce, Art & Alfred!
June 2018: Our team publishes on how NDM is evolving in the clinic to overcome zinc scarcity.
June 2018: Thanks to the Melanoma Research Foundation for the Cure Ocular Melanoma pilot grant!
May 2018: Corey (Postdoc Alumnus) earns tenure at Samford University. Congratulations! Well deserved!
April 2018: The Taxonomy of Covalent Inhibitors comes out – thanks Alfred – Kudos! We’ve been blogged and tweeted!
April 2018: Congrats to Lin-Cheng in the Crowder lab for his review in TIPS – Mechanism Matters!
February 2018: Congrats to Sean for his Outstanding Presentation Award in Medicinal Chemistry from the GCURS!
November 2017: Everett (PhD Alumnus) is named the 2017 UT Emerging Inventor of the Year. Kudos!
November 2017: Our team publishes on the mechanism of AMA inhibiting metallo-beta-lactamases.
October 2017: Alesha’s work on NDM-1 overcoming zinc scarcity is published and tweeted!
August 2017: Our team publishes a new NDM-1 inhibitor that works with clinical isolates.
July 2017: Best wishes to Alesha as she moves on to an APHL-CDC Postdoctoral Fellowship on Antimicrobial Resistance
July 2017: Best wishes to Ken (PhD Alumnus) as he moves on to AbbVie!
May 2017: Chris’s work on covalent protein modification by 4-halopyridines is published.
May 2017: Wishing Jake farewell at an Austin landmark as he heads to Yale Chemistry for grad school. We knew him when!
March 2017: Congrats to Alesha Stewart for her successful PhD defense! Kudos!
March 2017: Say Hi to the 2017 Library of Virtual Drug Screeners in the Freshman Research Initiative.
February 2017: Ken’s circular permutation to trap PvdQ substrate is published – check out his bio!
November 2016: Congrats to Chris Schardon for his successful PhD defense. Huzzah!
September 2016: Walt deletes “Associate” from his business card.
August 2016: Kudos to Ken Clevenger (PhD alumnus) for his funded F32: Functional proteoform-analysis of the glioma oncogene idh1
June 2016: Congrats to Oscar Villarreal for acceptance to the UT Houston/MD Anderson MD/PhD Program!
April 2016: Congrats to Gayle Burstein-Teitelbaum on her new position at the Wistar Institute!
April 2016: Congrats to Jake Swartzel for winning an Undergraduate Research Fellowship. Well deserved!
March 2016: Walt and his fellow ARFPers visit NIH and the National Academy of Sciences.
November 2015: Walt joins the AACP-Academic Research Fellows Program.
June 2015: Congrats to Oscar Villarreal for becoming a Beckman Scholar!
May 2015: Congrats to Joyce Er for her successful PhD defense. Yay Dr. Joyce!
May 2015: Walt starts as a PI for the Freshman Research Initiative, working with Josh Beckham (Res. Educator) on Virtual Drug Screening
April 2015: Congrats to Alesha Stewart for her fellowship from the American Association of University Women (Austin Branch)
April 2015: Our MBL grant got funded. Thanks to all involved! Mentions in UTexas News, Austin Business Journal
February 2015: A dubious honor from Environmental Health and Safety
2014 & Prior
November 2014: Kudos to Pei and Michael (in the Brodbelt lab) for making the inside cover of ChemBioChem
August 2014: Congrats to Ken as he starts his new postdoc at Northwestern with Neil Kelleher
June 2014: Congrats to Gayle as she starts her new position as a Technology Licensing Specialist at UT, Austin
September 2012: Tom’s fragment paper: We’ve been blogged!
Spring 2011: Download the Longhorn Pharmacy Focus article on some of our 3D molecular visualization efforts.
Countering Antibiotic Resistance Mechanisms
Summary: The rise of new antibiotic resistance mechanisms is a global clinical health threat. We are studying an unusual metal-dependent β-lactamase called NDM-1 that has spread world-wide since its discovery in 2008, that is now present in community-acquired infections, and that provides resistance against almost an entire class of antibiotics. We study how this catalyst works and how ligands interact with its metal center. There are currently no drugs that counter its activity, so in addition to learning the fundamental science behind this and related enzymes, our work also directly contributes to developing new therapeutics.
Clinical Variants of New Delhi Metallo-beta-Lactamase Are Evolving to Overcome Zinc Scarcity , 2017 ACS Infect Dis
Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-beta-Lactamase-1, 2017 J Med Chem
Blocking Interbacterial Signaling Pathways
Summary: Many Gram negative pathogens coordinate expression of virulence factors through interbacterial signaling pathways in a process known as “quorum-sensing.” We are studying enzymes that block quorum sensing by recognizing and degrading the chemical signals used for communication. Our study of these enzymes informs the basic science of dinuclear zinc sites in catalysis, provides biochemical tools for manipulating quorum-sensing systems, and explores the application of these enzymes and their variants as therapeutic proteins.
Substrate Trapping in the Siderophore Tailoring Enzyme PvdQ, 2017 ACS Chem Biol
Structure and Biochemical Characterization of AidC, a Quorum-Quenching Lactonase with Atypical Selectivity, 2015 Biochemistry
Regulation of Nitric Oxide Production Through Methylated Arginines
Summary: Nitric oxide production is dysregulated in a number of disease states including septic shock, idiopathic pulmonary fibrosis and some cancers including melanoma. We are studying a regulatory mechanism in which endogenous inhibitors of nitric oxide production are controlled by the activity of enzymes in the pentein superfamily, specifically the dimethylarginine dimethylaminohydrolases (DDAHs). We are studying the mechanism of these enzymes and developing novel and potent inhibitors as the first stage in developing new drugs. We are also interested in understanding the structure and reactivity of the entire pentein superfamily and how some of these enzymes catalyze a single hydrolytic reaction, some catalyze two sequential hydrolytic reactions, and others instead catalyze amidino-transfer reactions.
Developing an irreversible inhibitor of human DDAH-1, an enzyme upregulated in melanoma. 2014 ChemMedChem
Developing Novel Covalent Enzyme Inhibitors
Summary: Inhibitors that make covalent bonds with their target enzymes have many applications as tools in chemical biology, and also can have therapeutic applications. We are developing and studying covalent protein modifiers. Three examples for targets discussed above are 1) 2-chloroacetamidines as selective and potent inhibitors of DDAH, 2) n-alkylboronates as picomolar inhibitors of PvdQ, and 3) beta-lactam degradation products that covalently modify NDM-1. As a result of fragment-based high-throughput screening, we recently discovered that simple 2- and 4-halopyridines can serve as novel covalent modifiers that can selectively target select pairs of residues found in target proteins. We are studying their modification mechanisms, their targets, and their use in medicinal chemistry and chemical biology applications.
The Taxonomy of Covalent Inhibitors 2018 Biochemistry
Selective Covalent Protein Modification by 4-Halopyridines Through Catalysis 2017 ChemBioChem
On the mechanism of dimethylarginine dimethylaminohydrolase inactivation by 4-halopyridines. 2011 J Am Chem Soc
Please search PubMed for a list of publications from the Fast Lab.
The Taxonomy of Covalent Inhibitors
Metallo-β-Lactamases: Inhibitors and Reporter Substrates
The Enzymes of Bacterial Census and Censorship
Guanidine-Modifying Enzymes in the Pentein Superfamily
Publications not listed in PubMed:
Linsky TW, Fast W. Guanidine-Modifying Enzymes in the Pentein Superfamily, in Comprehensive Natural Products Chemistry II, Chemistry and Biology; Mander, L, Liu, H-w, Eds.; Elsevier: Oxford, 2010; volume 8, pp. 125-159.
Fast W. (Book Review of: PG Wang, TB Cai, & N Taniguchi Eds; “Nitric Oxide Donors for pharmaceutical and biological applications”, Weinheim, Germany: Wiley-VCH, 2005) in J Med Chem 2005, 48, 5056.
Huang H, Lee Y, Zhang HQ, Fast W, Riley B, Silverman RB. Selective Inhibition of Nitric Oxide Synthases. In Medicinal Chemistry into the Millennium; MM Campbell, IS Blagbrough, Eds.; Royal Society of Chemistry: Edinburgh, Scotland, 2001; Vol. 15, 303-328.
Fast W, Nikolic D, VanBreemen RB, Silverman RB. Mechanistic Studies of the Inactivation of Inducible Nitric Oxide Synthase by N5-(1-Iminoethyl)-L-ornithine (L-NIO). J Am Chem Soc 1999, 121, 903-916.
Fast W, Huff ME, Silverman RB. Time-Dependent Inhibition of Neuronal Nitric Oxide Synthase by N-Propargylguanidine. Bioorg Med Chem Lett 1997, 7, 1449-1454.
Current Lab Members
Past Lab Members
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Wet Lab Phone: (512) 471-5839
Lab Office Phone: (512) 232-8584
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University of Texas, Austin
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