Oral USC-093, a novel homoserinamide analogue of the tyrosinamide (S)-HPMPA prodrug USC-087 has decreased nephrotoxicity while maintaining antiviral efficacy against human adenovirus infection of Syrian hamsters.

Autor: Tollefson AE; Saint Louis University School of Medicine, St. Louis, MO, 63104, USA., Riemann SB; University of Southern California, Los Angeles, CA, 90089, USA., Ying B; Saint Louis University School of Medicine, St. Louis, MO, 63104, USA., Spencer JF; Saint Louis University School of Medicine, St. Louis, MO, 63104, USA., Overhulse JM; University of Southern California, Los Angeles, CA, 90089, USA., Kashemirov BA; University of Southern California, Los Angeles, CA, 90089, USA., Wold WSM; Saint Louis University School of Medicine, St. Louis, MO, 63104, USA., McKenna CE; University of Southern California, Los Angeles, CA, 90089, USA. Electronic address: mckenna@usc.edu., Toth K; Saint Louis University School of Medicine, St. Louis, MO, 63104, USA. Electronic address: karoly.toth@health.slu.edu.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2024 Feb; Vol. 222, pp. 105799. Date of Electronic Publication: 2024 Jan 06.
DOI: 10.1016/j.antiviral.2024.105799
Abstrakt: Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. Presently, there is no drug specifically approved for the treatment of adenovirus infections by the FDA. The state-of-the-art treatment of such infections is the off-label use of cidofovir, an acyclic nucleotide phosphonate. While cidofovir inhibits adenovirus replication, it has dose-limiting kidney toxicity. There is an apparent need for a better compound to treat adenovirus infections. To this end, we have been developing acyclic nucleotide phosphonate prodrugs that utilize an amino acid scaffold equipped with a lipophilic modifier. Here, we compare the antiviral potential of two prodrugs of HPMPA that differ only in the amino acid-based promoiety: USC-087, based on an N-hexadecyl tyrosinamide, and USC-093, based on an N-hexadecyl serinamide. Oral administration of both compounds was very efficacious against disseminated HAdV-C6 infection in immunosuppressed Syrian hamsters, suppressing virus replication and mitigating pathology even when treatment was withheld until 4 days after challenge. We saw only marginal efficacy after respiratory infection of hamsters, which may reflect suboptimal distribution to the lung. Importantly, neither compound induced intestinal toxicity, which was observed as the major adverse effect in clinical trials of brincidofovir, a prodrug of cidofovir which also contains a C-16 modifier. Notably, we found that there was a significant difference in the nephrotoxicity of the two compounds: USC-087 caused significant kidney toxicity while USC-093 did not, at effective doses. These findings will be valuable guidepoints in the future evolution of this new class of potential prodrugs to treat adenovirus infections.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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