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Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/jvi.02159-24· OSTI ID:2522033
 [1];  [1];  [2];  [1];  [3];  [3];  [4];  [1];  [1];  [5];  [6];  [1];  [7]
  1. University of Wisconsin, Madison, WI (United States)
  2. Columbia University Medical Center, New York, NY (United States
  3. University of Texas Medical Branch, Galveston, TX (United States). Galveston National Laboratory
  4. Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)
  5. University of Texas Medical Branch, Galveston, TX (United States)
  6. Columbia University Medical Center, New York, NY (United States); Università degli Studi della Campania Luigi Vanvitelli, Caserta (Italy)
  7. Columbia University Medical Center, New York, NY (United States)
+ Show Author Affiliations

SARS-CoV-2 poses an ongoing threat to human health as variants continue to emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated vaccines (only 22% received the 2023 update). Public hesitancy towards vaccines and common occurrence of “breakthrough” infections (i.e., infections of vaccinated individuals) highlight the need for alternative methods to reduce viral transmission. SARS-CoV-2 enters cells by fusing its envelope with the target cell membrane in a process mediated by the viral spike protein, S. The S protein operates via a Class I fusion mechanism in which fusion between the viral envelope and host cell membrane is mediated by structural rearrangements of the S trimer. We previously reported lipopeptides derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibit fusion by SARS-CoV-2, both in vitro and in vivo. These lipopeptides bear an attached cholesterol unit to anchor them in the membrane. Here, to improve prospects for experimental development and future clinical utility, we employed structure-guided design to incorporate charged residues at specific sites in the peptide to enhance aqueous solubility. This effort resulted in two new, potent lipopeptide inhibitors.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
Grant/Contract Number:
SC0012704
OSTI ID:
2522033
Report Number(s):
BNL--227607-2025-JAAM
Journal Information:
Journal of Virology, Journal Name: Journal of Virology Journal Issue: 3 Vol. 99; ISSN 0022-538X
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

36 MATERIALS SCIENCE
SARS-CoV-2
antiviral
crystal structure
heptad repeats
inhibitors
lipopeptide
peptide design
solubility
viral fusion