Clinical proteins, modified

Altered penicillin binding proteins Modified PBPs have a lower affinity for p-lactam antibiotics, requiring clinically unattainable concentrations of the drug to effect binding and inhibition of bacterial growth. This mechanism may explain methicillin-resistant staphylococci, although it does not explain its resistance to non-lactam antibiotics like erythromycin to which they are also refractory. 

The partitioning of the activated inhibitor between direct covalent inactivation of the enzyme and release into solution is an important issue for mechanism-based inactivators. The partition ratio is of value as a quantitative measure of inactivation efficiency, as described above. This value is also important in assessing the suitability of a compound as a drug for clinical use. If the partition ratio is high, this means that a significant proportion of the activated inhibitor molecules is not sequestered as a covalent adduct with the target enzyme but instead is released into solution. Once released, the compound can diffuse away to covalently modify other proteins within the cell, tissue, or systemic circulation. This could then lead to the same types of potential clinical liabilities that were discussed earlier in this chapter in the context of affinity labels, and would therefore erode the potential therapeutic index for such a compound. 

CPMV particles that contained a 17-mer neutralizing epitope, 3L17, from the VP2 capsid of Mink enteritis vims (MEV) fused to the S protein were generated. When mixed with adjuvant, these particles protected all the test animals from clinical disease when challenged with vimlent MEV. A modified constmct, which presented the... 

The clinical significance of protein-based impurities relates to (a) their potential biological activities and (b) their antigenicity. Whereas some contaminants may display no undesirable biological activity, others may exhibit activities deleterious to either the product itself (e.g. proteases that could modify/degrade the product) or the recipient patient (e.g. the presence of contaminating toxins). 

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