Preformulation Characterization of Griffithsin, a Biopharmaceutical Candidate for HIV Prevention.

Autor: Kramzer LF; Magee-Womens Research Institute, 204 Craft Avenue, Room B509, Pittsburgh, Pennsylvania, 15213, USA., Hamorsky KT; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA., Graebing PW; Magee-Womens Research Institute, 204 Craft Avenue, Room B509, Pittsburgh, Pennsylvania, 15213, USA., Wang L; Magee-Womens Research Institute, 204 Craft Avenue, Room B509, Pittsburgh, Pennsylvania, 15213, USA., Fuqua JL; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA., Matoba N; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA., Lasnik AB; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA., Moncla BJ; Magee-Womens Research Institute, 204 Craft Avenue, Room B509, Pittsburgh, Pennsylvania, 15213, USA.; Department of Obstetrics, Gynecology, & Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Zhang J; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Palmer KE; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA., Rohan LC; Magee-Womens Research Institute, 204 Craft Avenue, Room B509, Pittsburgh, Pennsylvania, 15213, USA. rohanlc@upmc.edu.; Department of Obstetrics, Gynecology, & Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. rohanlc@upmc.edu.; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. rohanlc@upmc.edu.
Jazyk: angličtina
Zdroj: AAPS PharmSciTech [AAPS PharmSciTech] 2021 Feb 24; Vol. 22 (3), pp. 83. Date of Electronic Publication: 2021 Feb 24.
DOI: 10.1208/s12249-021-01931-0
Abstrakt: Griffithsin (GRFT) has shown potent anti-HIV activity, and it is being developed as a drug candidate for HIV prevention. Successful implementation requires thorough understanding of its preformulation characterization. In this work, preformulation assessments were conducted to characterize GRFT and identify its degradation pathways under selected conditions of temperature, light, pH, shear, ionic strength, and oxidation. Compatibility with vaginal fluid simulant, vaginal enzymes, Lactobacillus spp., and human cervicovaginal secretions was assessed. The purity, melting temperature, and HIV gp120-binding affinity of GRFT stored at 4°C and 25°C in phosphate-buffered saline (PBS) were assessed for 2 years. Chemical modifications were evaluated by intact mass analysis and peptide sequencing. Excised human ectocervical tissue permeability and localization of GRFT were evaluated. Our results demonstrated GRFT to be safe and stable under all the preformulation assessment conditions studied except oxidative stress. When GRFT was exposed to hydrogen peroxide or human cervicovaginal secretion, methionine 78 in the protein sequence underwent oxidation. GRFT did not permeate through human cervical tissue but adhered to the superficial epithelial tissue. The 2-year stability study revealed no significant change in GRFT's aggregation, degradation, melting temperature, or gp120-binding affinity despite a slow increase in oxidation over time. These studies elucidated desirable safety and bioactivity profile for GRFT, showing promise as a potential drug candidate for HIV prevention. However, susceptibility to oxidative degradation was identified. Effective protection of GRFT from oxidation is required for further development.
Databáze: MEDLINE
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