2. Academic Validation
  3. Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors

Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors

  • J Med Chem. 2020 Jan 9;63(1):349-368. doi: 10.1021/acs.jmedchem.9b01737.
Belén Martínez-Gualda 1,  Liang Sun 2,  Olaia Martí-Marí 1,  Sam Noppen 2,  Rana Abdelnabi 2,  Carol M Bator 3,  Ernesto Quesada 1,  Leen Delang 2,  Carmen Mirabelli 2,  Hyunwook Lee 3,  Dominique Schols 2,  Johan Neyts 2,  Susan Hafenstein 3 4,  María-José Camarasa 1,  Federico Gago 5,  Ana San-Félix 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica (IQM-CSIC) , 28006 Madrid , Spain.
  • 2 Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy , University of Leuven , B-3000 Leuven , Belgium.
  • 3 Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences , The Pennsylvania State University , University Park , 16802 State College , Pennsylvania , United States.
  • 4 Department of Medicine , The Pennsylvania State University College of Medicine , 17033 Hershey , Pennsylvania , United States.
  • 5 Departamento de Ciencias Biomédicas y Unidad Asociada IQM-UAH , Universidad de Alcalá , Alcalá de Henares, E-28805 Madrid , Spain.
PMID: 31809045 DOI: 10.1021/acs.jmedchem.9b01737
Abstract

Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. The situation is even worse for Enterovirus EV71 Infection for which no Antiviral therapies are available. We describe here the discovery of potent entry dual inhibitors of HIV and EV71. These compounds contain in their structure three or four tryptophan (Trp) residues linked to a central scaffold. Critical for anti-HIV/EV71 activity is the presence of extra phenyl rings, bearing one or two carboxylates, at the C2 position of the indole ring of each Trp residue. The most potent derivatives, 22 and 30, inhibit early steps of the replicative cycles of HIV-1 and EV-A71 by interacting with their respective viral surfaces (glycoprotein gp120 of HIV and the fivefold axis of the EV-A71 capsid). The high potency, low toxicity, facile chemical synthesis, and great opportunities for chemical optimization make them useful prototypes for future medicinal chemistry studies.

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