Viral Entry and Egress

As an example of how an understanding of the intricate mechanisms of viral replication can drive therapeutic design, our lab, together with long-term collaborators in Germany, have demonstrated the critical role that proteolysis of viral envelope glycoproteins plays in successful viral entry for many viruses, inclusing the filo- and coronaviruses. Using this information, we have screened libraries of small molecule protease inhibitors in order to identify candidate compounds as therapeutics. Conversely, we are also using the phenomonen of anti-CHIKV antibodies blocking viral egress in order to probe the molecular mechanisms driving alphavirus particle formation and budding.

Selected Publications:

Steffen I, Simmons G. Pseudotyping Viral Vectors With Emerging Virus Envelope Proteins. Curr Gene Ther. (2016). 16(1):47-55. PMID: 26785737

Wrensch F, Karsten CB, Gnirß K, Hoffmann M, Lu K, Takada A, Winkler M, Simmons G, Pöhlmann S. Interferon-Induced Transmembrane Protein-Mediated Inhibition of Host Cell Entry of Ebolaviruses. J Infect Dis. (2015). 212 (Suppl 2):S210-8. PMCID:PMC4564551

Simmons G, Zmora P, Gierer S, Heurich A, Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research. Antiviral Res. (2013). 100:605-14. PMCID: PMC3889862.

Salvador B, Sexton NR, Carrion R, Nunneley J, Patterson JL, Steffen I, Lu K, Muench MO, Lembo D, Simmons G. Filoviruses utilize glycosaminoglycans for their attachment to target cells. J Virol (2013). 87:3295-304. PMCID: PMC3592117.

Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krämer-Kühl A, Welsch K, Winkler M, Meyer B, Drosten C, Dittmer U, von Hahn T, Simmons G, Hofmann H, Pöhlmann S. The spike-protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2 and is targeted by neutralizing antibodies. J Virol (2013). 87:5502-11. PMCID: PMC3648152.

Steffen I, Liss NM, Schneider BS, Fair JN, Chiu CY, Simmons G. Characterization of the Bas-Congo virus glycoprotein and its function in pseudotyped viruses. J Virol (2013). 87:9558-9568. PMCID: PMC3754090.

Zhou Y and Simmons G. Development of Novel Entry Inhibitors Targeting Emerging Viruses. Expert Rev. Anti Infect. Ther. (2012). 10:1129-38. PMCID: PMC3587779.

Zhou Y, Lu K, Pfefferle S, Bertram S, Glowacka I, Drosten C, Pöhlmann S, Simmons G. A Single Asparagine-Linked Glycosylation Site of the SARS-Coronavirus Spike Glycoprotein Facilitates Inhibition by Mannose-Binding Lectin through Multiple Mechanisms. J Virol (2010) 84:8753-64. PMCID: PMC2919028.

Kumaki Y, Wandersee MK, Smith AJ, Zhou Y, Simmons G, Nelson NM, Bailey KW, Vest ZG, Li JK, Chan PK, Smee DF, Barnard DL. Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin. Antiviral Res. (2011) 90:22-32. PMCID: PMC3085190.

Simmons G, Bertram S, Glowacka I, Steffen I, Chaipan C, Agudelo J, Lu K, Rennekamp AJ, Hofmann H, Bates P, Pöhlmann S. Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion. Virology (2011). 413:265-274. PMCID: PMC3086175.

Bertram S, Glowacka I, Müller M, Hayley L, Gnirß K, Nehlmeier I, Niemeyer D, He Y, Simmons G, Drosten C, Soilleux E, Jahn O, Steffen I, Pöhlmann S. Cleavage and activation of the SARS-coronavirus spike-protein by human airway trypsin-like protease (HAT). J Virol. (2011). 85:13363-13372. PMCID: PMC3233180.

Salvador B, Zhou Y, Michault A, Muench MO, Simmons G. Characterization of Chikungunya pseudotyped viruses: Identification of refractory cell lines and demonstration of cellular tropism differences mediated by mutations in E1 glycoprotein. Virology. (2009) 393:33-41. PMCID: PMC2760448.

Kaletsky RL, Simmons G, Bates P. Proteolysis of the Ebola glycoproteins enhances virus binding and infectivity. J Virol. (2007) 81:13378-84. PMCID: PMC2168880.

Marzi A, Akhavan A, Simmons G, Gramberg T, Hofmann H, Bates P, Lingappa VR, Pöhlmann S. The signal peptide of the ebolavirus glycoprotein influences interaction with the cellular lectins DC-SIGN and DC-SIGNR. J Virol. (2006) 80:6305-6317. PMCID: PMC1488929.

Hofmann H, Simmons G, Rennekamp AJ, Chaipan C, Gramberg T, Heck E, Geier M, Wegele A, Marzi A, Bates P, Pöhlmann S. Highly Conserved Regions within the Spike Proteins of Human Coronaviruses 229E and NL63 Determine Recognition of Their Respective Cellular Receptors. J Virol. (2006) 80:8639-8652. PMCID: PMC1563880.

Simmons G, Gosalia DN, Rennekamp AJ, Reeves JR, Diamond SL, Bates P. Inhibitors of cathepsin L prevent SARS coronavirus entry. PNAS. (2005) 102:11876-11881. PMCID: PMC1188015.

Simmons G, Reeves J, Rennekamp A, Amberg S, Piefer A, Bates P. Characterization of severe acute respiratory syndrome-associated coronavirus spike protein mediated viral entry. PNAS (2004) 101:4240-4245. PMCID: PMC384725.