Dr. Alexander Wlodawer

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Academic Career Length

33Years (1994-Present)

(Calculated once Scilit publication data is synced: current year − year of first publication + 1)

Representative Publications

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1 June 1998 in Annual Review of Biophysics

Journal Article

INHIBITORS OF HIV-1 PROTEASE: A Major Success of Structure-Assisted Drug Design

Alexander Wlodawer

Jiri Vondrasek

▪ Abstract Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.

6 December 2007 in The FEBS Journal

Journal Article

Protein crystallography for non‐crystallographers, or how to get the best (but not more) from published macromolecular structures

Alexander Wlodawer

Wladek Minor

Zbigniew Dauter

Mariusz Jaskólski

The number of macromolecular structures deposited in the Protein Data Bank now exceeds 45 000, with the vast majority determined using crystallographic methods. Thousands of studies describing such structures have been published in the scientific literature, and 14 Nobel prizes in chemistry or medicine have been awarded to protein crystallographers. As important as these structures are for understanding the processes that take place in living organisms and also for practical applications such as drug design, many non‐crystallographers still have problems with critical evaluation of the structural literature data. This review attempts to provide a brief outline of technical aspects of crystallography and to explain the meaning of some parameters that should be evaluated by users of macromolecular structures in order to interpret, but not over‐interpret, the information present in the coordinate files and in their description. A discussion of the extent of the information that can be gleaned from the coordinates of structures solved at different resolution, as well as problems and pitfalls encountered in structure determination and interpretation are also covered.

24 June 2005 in ChemBioChem

Journal Article

1,2,3‐Triazole as a Peptide Surrogate in the Rapid Synthesis of HIV‐1 Protease Inhibitors

Ashraf Brik

Jerry Alexandratos

Ying‐Chuan Lin

John H. Elder

Arthur J. Olson

Chi-Huey Wong

28 January 2021 in Nature Communications

Journal Article

A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Shin-ichiro Hattori

Nobuyo Higashi-Kuwata

Hironori Hayashi

Srinivasa Rao Allu

Jakka Raghavaiah

Hiroaki Mitsuya

+17

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (M^pro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC₅₀ values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with M^pro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead M^pro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

1 July 2006 in Structure

Journal Article

Domain-Swapped Structure of the Potent Antiviral Protein Griffithsin and Its Mode of Carbohydrate Binding

Natasza E. Ziółkowska

Barry R. O'Keefe

Toshiyuki Mori

Charles Zhu

Barbara Giomarelli

Alexander Wlodawer

1 March 2000 in Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology

Journal Article

Structural and biochemical studies of retroviral proteases

Alexander Wlodawer

Alla Gustchina

About Me

Alexander Wlodawer received his Ph.D. from the University of California, Los Angeles, in 1974. Having completed his postdoctoral training at Stanford University, he joined the National Bureau of Standards in 1976, then moved to the ABL-Basic Research Program at the NCI-FCRDC in 1987. From October 1998 to March 1999, he was on sabbatical as an elected Visiting Fellow of Sidney Sussex College, University of Cambridge. Dr. Wlodawer was Chief of the former Macromolecular Crystallography Laboratory, CCR, NCI from 1999 to 2020, and is currently a Senior Investigator in the Center for Structural Biology. Dr. Wlodawer is Doctor Honoris Causa of the Technical University of Lodz, Poland. He was elected a Foreign Member of the Polish Academy of Sciences in 2005, is a recipient of the 2006 NCI Mentor of Merit Award, and was awarded the Heyrovsky Honorary Medal by the Czech Academy of Sciences in 2008, a Polish-American scientific collaboration award in 2015, and the Casimir Funk award in 2024. He is a member of the American Crystallographic Association and was elected ACA Fellow in 2013. He has served as an Editor of the FEBS Journal since 2007, as an Associate Editor of FEBS OpenBio since 2011, and as Editor-in-Chief of the Current Research in Structural Biology since 2021.

Dr. Alexander Wlodawer

Dr. Alexander Wlodawer

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