My laboratory investigates the role that viral proteins, particularly viral proteases, play in remodeling host cells and creating a favorable environment for virus replication. To this end, we take a two-pronged approach: employ modern systems biology methods to get a global view of the virus-host interface and then use classical molecular biology and biochemistry techniques to gain deeper mechanistic insights.
The major focus of my laboratory is to identify and characterize host proteins that are cleaved by viral proteases. For this, we use a relatively unbiased approach to label and capture protein N-termini generated by proteolytic cleavage in virus-infected cells. This powerful proteomics (“degradomics”) approach not only identifies the cleaved proteins but also the site of cleavage within a protein. Once the proteins are identified and their cleavage is validated by orthogonal methods, we then ascertain the functional significance of these cleavages in the virus life cycle.
Besides studying host proteins that we have identified from the degradomics analysis of clinically important enteroviruses, we continue to extend this analysis to viruses from other families with the goal to get a global view of cellular pathways commonly targeted or co-opted by diverse viruses. These studies are expected to provide novel insights into cell biology, antiviral defenses, and disease mechanisms. Also, viral proteases are one of the prime targets for antiviral development, and therefore deeper insights into their function will help improve viral therapeutics.
Laboratory Members
Research positions are available, please contact Dr. Saeed.
Representative Publications
-
Ren W, Zhu Y, Lan J, Chen H, Wang Y, Shi H, Feng F, Chen DY, Close B, Zhao X, Wu J, Tian B, Yuan Z, Zhou D, Saeed M, Wang X, Zhang R, Ding Q. Susceptibilities of human ACE2 genetic variants in coronavirus infection. J Virol. 2021 Oct 20; JVI0149221. PMID: 34668773
-
Chen DY, Khan N, Close BJ, Goel RK, Blum B, Tavares AH, Kenney D, Conway HL, Ewoldt JK, Chitalia VC, Crossland NA, Chen CS, Kotton DN, Baker SC, Fuchs SY, Connor JH, Douam F, Emili A, Saeed M. SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway. J Virol. 2021 09 09; 95(19):e0086221. PMID: 34260266;
-
Nageswara Rao D, Zephyr J, Henes M, Chan ET, Matthew AN, Hedger AK, Conway HL, Saeed M, Newton A, Petropoulos CJ, Huang W, Kurt Yilmaz N, Schiffer CA, Ali A. Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants. J Med Chem. 2021 08 26; 64(16):11972-11989. PMID: 34405680
-
Kim S, Yee E, Miller EA, Hao Y, Tay DMY, Sung KJ, Jia H, Johnson JM, Saeed M, Mace CR, Yüksel Yurt D, Sikes HD. Developing a SARS-CoV-2 Antigen Test Using Engineered Affinity Proteins. ACS Appl Mater Interfaces. 2021 Aug 25; 13(33):38990-39002. PMID: 34379400
-
Weingarten-Gabbay S, Klaeger S, Sarkizova S, Pearlman LR, Chen DY, Gallagher KME, Bauer MR, Taylor HB, Dunn WA, Tarr C, Sidney J, Rachimi S, Conway HL, Katsis K, Wang Y, Leistritz-Edwards D, Durkin MR, Tomkins-Tinch CH, Finkel Y, Nachshon A, Gentili M, Rivera KD, Carulli IP, Chea VA, Chandrashekar A, Bozkus CC, Carrington M, Bhardwaj N, Barouch DH, Sette A, Maus MV, Rice CM, Clauser KR, Keskin DB, Pregibon DC, Hacohen N, Carr SA, Abelin JG, Saeed M, Sabeti PC. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell. 2021 07 22; 184(15):3962-3980.e17. PMID: 34171305; PMCID: PMC8173604; DOI: 10.1016/j.cell.2021.05.046;
-
Bandyopadhyay S, Douglass J, Kapell S, Khan N, Feitosa-Suntheimer F, Klein JA, Temple J, Brown-Culbertson J, Tavares AH, Saeed M, Lau NC. DNA templates with blocked long 3′ end single-stranded overhangs (BL3SSO) promote bona fide Cas9-stimulated homology-directed repair of long transgenes into endogenous gene loci. G3 (Bethesda). 2021 May 14. PMID: 33989385
-
Sanders DW, Jumper CC, Ackerman PJ, Bracha D, Donlic A, Kim H, Kenney D, Castello-Serrano I, Suzuki S, Tamura T, Tavares AH, Saeed M, Holehouse AS, Ploss A, Levental I, Douam F, Padera RF, Levy BD, Brangwynne CP. SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation. Elife. 2021 04 23; 10.PMID: 33890572
-
Kim S, Yee EH, Miller EA, Hao Y, Tay DMY, Sung KJ, Jia H, Johnson JM, Saeed M, Mace CR, Yurt DY, Sikes H. Developing a SARS-CoV-2 Antigen Test Using Engineered Affinity Proteins. ChemRxiv. 2021 Apr 19. PMID: 34013166
-
Loffredo M, Lucero H, Chen DY, O’Connell A, Bergqvist S, Munawar A, Bandara A, De Graef S, Weeks SD, Douam F, Saeed M, Munawar AH. The in-vitro effect of famotidine on sars-cov-2 proteases and virus replication. Sci Rep. 2021 03 08; 11(1):5433. PMID: 33686143
-
O’Brien A, Chen DY, Hackbart M, Close BJ, O’Brien TE, Saeed M, Baker SC. Detecting SARS-CoV-2 3CLpro expression and activity using a polyclonal antiserum and a luciferase-based biosensor. Virology. 2021 04; 556:73-78. PMID: 33548599
-
Carossino M, Montanaro P, O’Connell A, Kenney D, Gertje H, Grosz KA, Kurnick SA, Bosmann M, Saeed M, Balasuriya UBR, Douam F, Crossland NA. Fatal neuroinvasion of SARS-CoV-2 in K18-hACE2 mice is partially dependent on hACE2 expression. bioRxiv. 2021 Jan 15. PMID: 33469581
-
Hekman RM, Hume AJ, Goel RK, Abo KM, Huang J, Blum BC, Werder RB, Suder EL, Paul I, Phanse S, Youssef A, Alysandratos KD, Padhorny D, Ojha S, Mora-Martin A, Kretov D, Ash PEA, Verma M, Zhao J, Patten JJ, Villacorta-Martin C, Bolzan D, Perea-Resa C, Bullitt E, Hinds A, Tilston-Lunel A, Varelas X, Farhangmehr S, Braunschweig U, Kwan JH, McComb M, Basu A, Saeed M, Perissi V, Burks EJ, Layne MD, Connor JH, Davey R, Cheng JX, Wolozin BL, Blencowe BJ, Wuchty S, Lyons SM, Kozakov D, Cifuentes D, Blower M, Kotton DN, Wilson AA, Mühlberger E, Emili A. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. Mol Cell. 2021 Jan 07; 81(1):212. PMID:
33417854
-
Brown RJP, Tegtmeyer B, Sheldon J, Khera T, Anggakusuma, Todt D, Vieyres G, Weller R, Joecks S, Zhang Y, Sake S, Bankwitz D, Welsch K, Ginkel C, Engelmann M, Gerold G, Steinmann E, Yuan Q, Ott M, Vondran FWR, Krey T, Ströh LJ, Miskey C, Ivics Z, Herder V, Baumgärtner W, Lauber C, Seifert M, Tarr AW, McClure CP, Randall G, Baktash Y, Ploss A, Thi VLD, Michailidis E, Saeed M, Verhoye L, Meuleman P, Goedecke N, Wirth D, Rice CM, Pietschmann T. Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice. Sci Adv. 2020 Nov; 6(45). PMID:
33148654
-
Chen DY, Khan N, Close BJ, Goel RK, Blum B, Tavares AH, Kenney D, Conway HL, Ewoldt JK, Kapell S, Chitalia VC, Crossland NA, Chen CS, Kotton DN, Baker SC, Connor JH, Douam F, Emili A, Saeed M. SARS-CoV-2 desensitizes host cells to interferon through inhibition of the JAK-STAT pathway. bioRxiv. 2020 Oct 28. PMID:
33140044
-
Weingarten-Gabbay S, Klaeger S, Sarkizova S, Pearlman LR, Chen DY, Bauer MR, Taylor HB, Conway HL, Tomkins-Tinch CH, Finkel Y, Nachshon A, Gentili M, Rivera KD, Keskin DB, Rice CM, Clauser KR, Hacohen N, Carr SA, Abelin JG, Saeed M, Sabeti PC. SARS-CoV-2 infected cells present HLA-I peptides from canonical and out-of-frame ORFs. bioRxiv. 2020 Oct 02. PMID:
33024965
-
Saeed M, Kapell S, Hertz NT, Wu X, Bell K, Ashbrook AW, Mark MT, Zebroski HA, Neal ML, Flodström-Tullberg M, MacDonald MR, Aitchison JD, Molina H, Rice CM. Defining the proteolytic landscape during enterovirus infection. PLoS Pathog. 2020 09; 16(9):e1008927. PMID:
32997711
-
Huang J, Hume AJ, Abo KM, Werder RB, Villacorta-Martin C, Alysandratos KD, Beermann ML, Simone-Roach C, Lindstrom-Vautrin J, Olejnik J, Suder EL, Bullitt E, Hinds A, Sharma A, Bosmann M, Wang R, Hawkins F, Burks EJ, Saeed M, Wilson AA, Mühlberger E, Kotton DN. SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response. Cell Stem Cell. 2020 12 03; 27(6):962-973.e7. PMID:
32979316
-
Ejemel M, Li Q, Hou S, Schiller ZA, Tree JA, Wallace A, Amcheslavsky A, Kurt Yilmaz N, Buttigieg KR, Elmore MJ, Godwin K, Coombes N, Toomey JR, Schneider R, Ramchetty AS, Close BJ, Chen DY, Conway HL, Saeed M, Ganesa C, Carroll MW, Cavacini LA, Klempner MS, Schiffer CA, Wang Y. A cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction. Nat Commun. 2020 08 21; 11(1):4198. PMID:
32826914
-
Pfaender S, Mar KB, Michailidis E, Kratzel A, Boys IN, V’kovski P, Fan W, Kelly JN, Hirt D, Ebert N, Stalder H, Kleine-Weber H, Hoffmann M, Hoffmann HH, Saeed M, Dijkman R, Steinmann E, Wight-Carter M, McDougal MB, Hanners NW, Pöhlmann S, Gallagher T, Todt D, Zimmer G, Rice CM, Schoggins JW, Thiel V. LY6E impairs coronavirus fusion and confers immune control of viral disease. Nat Microbiol. 2020 11; 5(11):1330-1339. PMID:
32704094
-
Esswein SR, Gristick HB, Jurado A, Peace A, Keeffe JR, Lee YE, Voll AV, Saeed M, Nussenzweig MC, Rice CM, Robbiani DF, MacDonald MR, Bjorkman PJ. Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody. Proc Natl Acad Sci U S A. 2020 05 05; 117(18):9865-9875. PMID:
32321830
-
Dao Thi VL, Wu X, Belote RL, Andreo U, Takacs CN, Fernandez JP, Vale-Silva LA, Prallet S, Decker CC, Fu RM, Qu B, Uryu K, Molina H, Saeed M, Steinmann E, Urban S, Singaraja RR, Schneider WM, Simon SM, Rice CM. Stem cell-derived polarized hepatocytes. Nat Commun. 2020 04 03; 11(1):1677. PMID:
32245952