Comparison of Cytomegalovirus Terminase Gene Mutations Selected after Exposure to Three Distinct Inhibitor Compounds [PublishAheadOfPrint]

Letermovir, GW275175X (a benzimidazole) and tomeglovir (Bay38-4766) are chemically unrelated human cytomegalovirus (CMV) terminase complex inhibitors that have been tested in human subjects. UL56 gene mutations are the dominant pathway of letermovir resistance, while UL89 and UL56 mutations are known to confer benzimidazole resistance. This study compares the mutations elicited by the three inhibitors during in vitro CMV propagation. GW275175X consistently selected for UL89 D344E, and sometimes UL89 C347S, R351H, or UL56 Q204R. Tomeglovir consistently selected for UL89 V362M, and sometimes UL89 N329S, T350M, H389N, N405D, or UL56 L208M, E407D, H637Q or V639M. Adding to known and novel UL56 mutations, letermovir occasionally selected for UL89 N320H, D344E or M359I. Recombinant phenotyping confirmed that UL89 D344E conferred 9-fold resistance (increased EC50) for GW275175X, and increased the letermovir and tomeglovir EC50 by 1.7 to 2.1-fold for baseline virus and UL56 mutants Q204R, E237D, F261L and M329T. UL89 N320H and M359I conferred <2-fold letermovir resistance but 7-fold resistance for tomeglovir; mutant N320H was also 4-fold resistant to GW275175X. UL89 N329S conferred tomeglovir and letermovir cross-resistance. UL89 T350M conferred resistance to all three inhibitors. UL89 C347S conferred 27-fold GW275175X resistance. UL89 V362M and H389N conferred 98-fold and 29-fold tomeglovir resistance without cross-resistance. Thus, characteristic UL89 mutations confer substantial resistance to GW275175X and tomeglovir, and are an uncommon accessory pathway of letermovir resistance. Instances of moderate cross-resistance and proximity of the selected UL89 and UL56 mutations suggest targeting of a similar terminase functional locus involving UL56 and UL89 interaction.

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