BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME Kalyan Das	POSITION TITLE Research Professor
eRA COMMONS USER NAME kalyan_das	POSITION TITLE Research Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION	DEGREE (if applicable)	YEAR(s)	FIELD OF STUDY
Berhampur University, India	M.S.	1984	Solid State Physics
Indian Institute of Technology (IIT), Bombay, India	Ph.D.	1991	X-ray Crystallography
Molecular Biophysics Unit, Indian Institute of Science (IISc), Bangalore, India Center for Advanced Biotechnology & Medicine and Rutgers University	Postdoc Postdoc	1992-4 1994-6	Structural biology Structural biology, drug resistance and drug design

Research Interest

Understanding drug resistance, antiviral design, viral and bacterial transcription, identification and validation of new drug targets, understanding and targeting protein-protein interactions, molecular modeling and X-ray crystallography. Seeking active collaborations with industry and academia groups on above listed areas.

A. Personal Statement

For the past eighteen years, I have been actively engaged in pursuing and leading several multidisciplinary projects: (i) to understand molecular mechanisms of viral and bacterial drug resistance, (ii) to elucidate catalytic reaction mechanisms of enzymes – polymerases, human capping enzyme, and arginine deiminase, (iii) to identify drug targets, (iv) molecular modeling of protein:protein and protein:nucleic acid complexes, (v) docking of small molecules into target sites, and (vi) in drug discovery targeting HIV-1 reverse transcriptase. Outcomes of these research projects have been published in several leading peer-reviewed international journals.

A1. Molecular mechanism of drug resistance: Use of structural biology, biophysics, biochemistry and computational biology for understanding clinically emerging drug resistance mutations. For past seventeen years my colleagues and I have been engaged in understanding the molecular mechanisms of drug resistance by HIV-1 reverse transcriptase (RT) and hepatitis B polymerase, synergistic and antagonistic relationships among drug resistance mutations, and compensatory mutations in improving fitness of a drug-resistant mutant enzyme/virus. This understanding benefits development of new drugs and therapeutic strategies.

A2. Drug design: I have contributed to the development of anti-AIDS drugs Etravirine (TMC125) and Rilpivirine (TMC278), and developed a novel structure-based drug design concept (structural flexibility of inhibitors targeting drug-resistant mutants) that aided the design of this DAPY class non-nucleoside RT inhibitors. The structural flexibility in drug design has implications in targeting a broad range of viral and bacterial targets. RNA polymerase of bacteria, including Mycobacterium tuberculosis, has a novel hydrophobic myxopyronin-binding site against which antibiotic can be designed. Macrolide antibiotics bind to the large ribosomal subunit, and methylations at specific rRNA sites develop resistance to macrolide drugs. We proposed blocking methyl-transferases that are responsible for such methylations, as potential targets for co-drugs for suppressing macrolide resistance.

A3. Molecular targets of influenza A: Binding of non-structural protein NS1 of influenza A to human factor CPSF30 is important for suppressing the production of interferon b. Our crystal structure, biochemical, and recombinant virus studies revealed a NS1 site that can be targeted by chemotherapeutic agents for developing novel influenza A drugs. The emergence of H1N1 pandemic, looming threat of H5N1, and emerging drug-resistant influenza A strains demonstrate the urgent need for new flu drugs. We have recently reviewed the existing and emerging molecular targets in influenza A for designing antivirals.

B. Positions and Honors

Positions and Employment

1996-1998: Research Associate, Center for Advanced Biotechnology & Medicine (CABM), and Department of Chemistry, Rutgers University, NJ

1998-2001: Assistant Research Professor, CABM and Rutgers University

2001-2007: Associate Research Professor, CABM and Department of Chemistry, Rutgers University

2007- present Research Professor, CABM and Department of Chemistry, Rutgers University

Honors and Awards

1986-1988 Junior Research Fellowship at IIT, Bombay, India

1988-1991 Senior Research Fellowship at IIT, Bombay, India

1991 Research Associate Fellowship at IIT, Bombay, India

1992-1994 Postdoctoral fellowship at IISc, Bangalore, India

1994-1995 Postdoctoral Fellowship at CABM, Piscataway, New Jersey

1995-1996 Postdoctoral Associate Fellowship at CABM, Piscataway, New Jersey

2000 Certificate of Excellence for Outstanding Contribution to Hepatitis Research, April 2000 at 10^th International Symposium on Viral Hepatitis and Liver Disease.

2004 Contributed to the development of anti-AIDS drugs Etravirine (TMC125) and developed the novel structure-based drug design concept (structural flexibility of inhibitors targeting drug-resistant mutants) that aided the design of TMC125 and related DAPY class of inhibitors.

Invited speaker at several meetings and conferences.

Patent Applications

1. RIBOSOMAL RNA METHYLTRANSFERASES R1mA: TARGET VALIDATION AND PROCESSES FOR DEVELOPING AN INHIBITOR ASSAY AND IDENTIFICATION CANDIDATE INHIBITORS. With Montelione, G.T. and Arnold, E.

2. HIV REVERSE TRANSCRIPTASE COMPOSITIONS AND METHODS. With E. Arnold and Bauman J.

3. INFLUENZA A VIRUS VACCINES AND INHIBITORS. With Montelione, G.T., Arnold, E., Ma, L.-C., Rong X., Krug, R.M., Twu, K.Y., and Rei-Iin, K.

Professional Membership

· American Association of Advancement of Science (AAAS)

· American Chemical Society (ACS)

· Bangladesh Society for Biochemistry and Molecular Biology – Honorary membership

C. Selected peer-reviewed publications (Selected from 90 peer-reviewed publications and reviews)

1. Das, K., Xiong, X., Yang, H., Westland, C.E., Gibbs, C.S., Sarafianos, S.G., and Arnold E. (2001). Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). J. Virol. 75:4771-4779. PMCID: PMC114232.

2. Das, K., Clark, Jr., A.D., Lewi, P., Heeres, J., de Jonge, M., Koymans, L., Vinkers, M., Daeyaert, F., Ludovici, D.W., Kukla, M.J., De Corte, B., Kavash, R.W., Ho, C., Ye, H., Lichtenstein, M.A., Andries, K., Pauwels, R., de Bethune, M.-P., Boyer, P.L., Clark, P., Hughes, S.H., Janssen, P.A.J., and Arnold. E. (2004). Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (Etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem. 47:2550-2560. PMID: 15115397.

3. Das, K., Acton, T., Chiang, Y., Shih, L., Arnold, E., and Montelione, G.T. (2004). Crystal structure of RlmA^I: implications for understanding the 23S rRNA G745/G748-Methylation at the macrolide antibiotic binding site. Proc. Natl. Acad. Sci. USA. 101:4041-4046. PMCID: PMC384692.

4. Das, K., Butler, G.H., Kwiatkowski, V., Clark, Jr. A.D.Jr, Yadav, P., Arnold, E. (2004). Crystal structures of arginine deiminase with covalent reaction intermediates; implications for catalytic mechanism. Structure (Camb.) 12:657-667. PMID: 15062088.

5. Janssen, P. A., Lewi, P. J., Arnold, E., Daeyaert, F., de Jonge, M., Heeres, J., Koymans, L., Vinkers, M., Guillemont, J., Pasquier, E., Kukla, M., Ludovici, D., Andries, K., de Bethune, M. P., Pauwels, R., Das, K., Clark, A. D., Jr., Frenkel, Y. V., Hughes, S. H., Medaer, B., De Knaep, F., Bohets, H., De Clerck, F., Lampo, A., Williams, P., and Stoffels, P. (2005) In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine), J. Med. Chem. 48:1901-1909. PMID: 15771434.

6. Frenkel, Y.V., Clark, Jr. A.D., Das, K., Wang, Y-H, Lewi, P., Janssen, P.A.J., and Arnold, E. (2005). Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability. J. Med. Chem. 48:1974-1983. PMID: 15771441.

7. Das, K., Lewi,P.J., Hughes,S.H, Arnold,E. (2005). Crystallography and the design of anti-AIDS drugs: Conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog. Biophy. Mol. Biol. 88:209-231. PMID: 15572156.

8. Das, K., Sarafianos, S.G., Clark, Jr, A.D., Boyer, P.L., Hughes, S.H., Arnold, E. (2007). Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097. J. Mol. Biol. 365:77-89. PMID: 17056061.

9. Das, K., Bauman, J.D., Clark Jr., A.D., Frenkel, Y.V., Lewi, P.J., Shatkin, A.J., Hughes, S.H., Arnold, E. (2008). High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc. Natl. Acad. Sci. USA. 105:1466-1471. PMCID: PMC2234167.

10. Mukhopadhyay, J., Das, K., Ismail, S., Koppstein, D., Jang, M., Hudson, B., Sarafianos, S., Tuske, S., Patel, J.,Jansen, R., Irschik, H., Arnold, E., Ebright, R.H. (2008). The RNA polymerase “switch region” is a target for inhibitors. Cell 135:295-307. PMCID: PMC2580802.

11. Das, K., Ma, L.-C., Xiao, R., Radvansky, B., Aramini, J., Zhao, L., Marklung, J., Kuo, R.-L., Twu, K., Arnold, E., Krug, R., Montelione, G. (2008). Structural basis for suppression of a host antiviral response by influenza A virus. Proc. Natl. Acad. Sci. USA. 105:13092-13097. PMCID: PMC2522260.

12. Bauman, J.D., Das, K., Ho, W.C., Baweja, M., Himmel, D.M., Clark, Jr, A.D., Boyer, P.L., Hughes, S.H., and Arnold, E. (2008). Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design. Nucleic Acid Res. 36:5083-5092. PMCID: PMC2528191.

13. Das, K., Bandwar, R.P., White, K.L., Feng, J.Y., Sarafianos, S.G., Tuske, S., Tu, X., Clark, Jr., A.D., Boyer, P.L., Hou, X., Gaffney, B.L., Jones, R.A., Miller, M.D., Hughes, S.H., Arnold, E. (2009). Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance. J. Biol. Chem. 284:35092-35100. PMCID: PMC2787370.

14. Das, K., Aramini, J.M., Ma, L.-C., Krug, R., Arnold, E. (2010). Structures of Influenza A proteins and insights into antiviral targets. Nat. Struct. Mol. Biol. 17:530-538. PMCID: PMC2957899.

15. Tu, X, Das, K., Han, Q., Bauman, J.D., Clark, Jr., A.D., Hou, X., Frankel, Y.V., Gaffney, B.L., Jones, R.A., Boyer, P.L., Hughes, S.H., Sarafianos, S.H., Arnold, E. (2010). Structural basis of HIV-1 resistance to AZT by excision. Nat. Struct. Mol. Biol. 17:1202-1209. PMCID: PMC2987654.

D. Research Support:

Ongoing Research Support

Funding agency: NIH-NIAID

Defining and Targeting the HIV Nucleoside-Competing RT Inhibitor Binding Site.

Picture Galleries

· Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) design – A lesson for targeting drug resistance.

· Selected pictures of HIV-1 RT.

[Complete list of publications in scientific journals]

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BIOGRAPHICAL SKETCH

4. Das, K., Butler, G.H., Kwiatkowski, V., Clark, Jr. A.D.Jr, Yadav, P., Arnold, E. (2004). Crystal structures of arginine deiminase with covalent reaction intermediates; implications for catalytic mechanism. Structure (Camb.) 12:657-667. PMID: 15062088.

8. Das, K., Sarafianos, S.G., Clark, Jr, A.D., Boyer, P.L., Hughes, S.H., Arnold, E. (2007). Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097. J. Mol. Biol. 365:77-89. PMID: 17056061.