2. Academic Validation
  3. Synthesis and antiviral activity of fatty acyl conjugates of remdesivir against severe acute respiratory syndrome coronavirus 2 and Ebola virus

Synthesis and antiviral activity of fatty acyl conjugates of remdesivir against severe acute respiratory syndrome coronavirus 2 and Ebola virus

  • Eur J Med Chem. 2021 Dec 15:226:113862. doi: 10.1016/j.ejmech.2021.113862.
Naglaa Salem El-Sayed 1,  Alexander S Jureka 2,  Megan R Edwards 2,  Sandeep Lohan 3,  Caroline G Williams 2,  Patrick T Keiser 4,  Robert A Davey 4,  Jennifer Totonchy 5,  Rakesh K Tiwari 6,  Christopher F Basler 7,  Keykavous Parang 8
Affiliations

Affiliations

  • 1 Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA; AJK Biopharmaceutical, 5270 California Ave, Irvine, CA, 92617, USA; Cellulose & Paper Department, National Research Centre, 33 El-Bohouth St. former (El-Tahrir St.), Dokki, Giza P.O. Box, 12622, Egypt.
  • 2 Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, 686 Petit Science Center, Atlanta, GA, 30302, USA.
  • 3 Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA; AJK Biopharmaceutical, 5270 California Ave, Irvine, CA, 92617, USA.
  • 4 NEIDL, 620 Albany St, Boston University, Boston, MA, 02118, USA.
  • 5 Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA.
  • 6 Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA; AJK Biopharmaceutical, 5270 California Ave, Irvine, CA, 92617, USA. Electronic address: tiwari@chapman.edu.
  • 7 Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, 686 Petit Science Center, Atlanta, GA, 30302, USA. Electronic address: cbasler@gsu.edu.
  • 8 Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA; AJK Biopharmaceutical, 5270 California Ave, Irvine, CA, 92617, USA. Electronic address: parang@chapman.edu.
PMID: 34583312 DOI: 10.1016/j.ejmech.2021.113862
Abstract

We report here the synthesis, purification, and characterization of mono- and di-fatty acyl conjugates of remdesivir (RDV) and their in vitro Antiviral activity against SAR-CoV-2, an Ebola virus transcription- and replication-competent virus-like particle (trVLP) system, and infectious Ebola virus. The most potent monofatty acyl conjugate was 4b, containing a 4-oxatetradecanolyl at the 3' position. Monofatty acyl conjugates, 3'-O-tetradecanoyl (4a) (IC50(VeroE6) = 2.3 μM; IC50(Calu3) = 0.24 μM), 3'-O-4-oxatetradodecanoyl (4b) (IC50(VeroE6) = 2.0 μM; IC50(Calu3) = 0.18 μM), and 3'-O-(12-ethylthiododecanoyl) (4e) (IC50(VeroE6) = 2.4 μM; IC50(Calu3) = 0.25 μM) derivatives exhibited less activity than RDV (IC50(VeroE6) = 0.85 μM; IC50(Calu3) = 0.06 μM) in both VeroE6 and Calu3 cells. Difatty acylation led to a significant reduction in the Antiviral activity of RDV (as shown in conjugates 5a and 5b) against SARS-CoV-2 when compared with monofatty acylation (3a-e and 4a-e). About 77.9% of 4c remained intact after 4 h incubation with human plasma while only 47% of parent RDV was observed at the 2 h time point. The results clearly indicate the effectiveness of fatty acylation to improve the half-life of RDV. The Antiviral activities of a number of monofatty acyl conjugates of RDV, such as 3b, 3e, and 4b, were comparable with RDV against the Ebola trVLP system. Meanwhile, the corresponding physical mixtures of RDV and fatty acids 6a and 6b showed 1.6 to 2.2 times less Antiviral activity than the corresponding conjugates, 4a and 4c, respectively, against SARS-CoV-2 in VeroE6 cells. A significant reduction in viral RNA synthesis was observed for selected compounds 3a and 4b consistent with the IC50 results. These studies indicate the potential of these compounds as long-acting Antiviral agents or prodrugs of RDV.

Keywords

EBOV; Ebola virus; Fatty acyl-RDV conjugates; Remdesivir; SARS-CoV-2; Structure-activity relationships (SAR).

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