Abstract:
:The pneumococcal histidine triad protein D (PhtD) is believed to play a central role in pneumococcal metal ion homeostasis and has been proposed as a promising vaccine candidate against pneumococcal disease. To investigate for potential stabilizers, a panel of physiologically relevant metals was screened using the thermal shift assay and it was found that only Zn2+ and Mn2+ were able to increase PhtD melting temperature. Differential scanning calorimetry analysis revealed a sequential unfolding of PhtD and the presence of at least 3 independent folding domains that can be stabilized by Zn2+ and Mn2+. UV spectroscopy and fluorescence quenching studies showed significant Zn2+-induced tertiary structure changes in PhtD characterized by decreased accessibility of inner tryptophan residues to the aqueous solvent. Isothermal titration calorimetry data show no apparent binding to Mn2+ but revealed a Zn2+:PhtD exothermic interaction stoichiometry of 3:1 with strong enthalpic contribution, suggesting that 3 of the 5 histidine triads are accessible binding sites for Zn2+. Only Zn+2, but not Mn+2, was able to increase the thermal stability of PhtD in the presence of aluminum hydroxide adjuvant, making it a promising stabilizer excipient candidate in vaccine products containing PhtD.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Ausar SF,Jayasundara K,Akawi L,Roque C,Sheung A,Hu J,Kirkitadze M,Rahman Ndoi
10.1016/j.xphs.2017.06.003subject
Has Abstractpub_date
2017-10-01 00:00:00pages
2979-2987issue
10eissn
0022-3549issn
1520-6017pii
S0022-3549(17)30439-2journal_volume
106pub_type
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