Indicating that the prescribed dose of zanamivir is not sufficient to inhibit bacterial neuraminidases. Therefore, if a certain amount of neuraminidase activity, originating from bacteria, is present on the surface of the respiratory tract, influenza virus infection, release and spread may not be suppressed by NA inhibitor drugs. In agreement with this possibility, it has been reported that receiving professional oral care and oral health guidance from a dental hygienist reduces both the number of oral bacteria and the activities of neuraminidase in saliva, resulting in a reduction in the risk of infection from influenza. Altogether, the control of bacterial neuraminidases in the upper respiratory tract should be taken in consideration when using prescribed NA inhibitors in order to minimize reduced drug potency. Both of these domains recognize the phospho-Ser/Thr-Pro bonds present in mitotic phosphoproteins. Pin1 is distinct from two other PPIase families, cyclophilin and FK506 binding protein, since Pin1 only has PPIase activity for phosphorylated substrates. Pin1 catalyzes prolyl cis-trans isomerization to function as a FDA-approved Compound Library molecular timer regulating the cell cycle, cell signaling, gene expression, immune response, and neuronal function. Pin1 is overexpressed in many cancer lines, and plays an important role in oncogenesis. Because of its significant role in cell cycle regulation by a unique mechanism, Pin1 represents an intriguing diagnostic and therapeutic target for cancer. Several promising classes of Pin1 inhibitors have been synthesized as potential lead compounds, including designed inhibitors, and natural products. The mechanisms of the PPIases, cyclophilins and FKBPs, were shown to go through a twisted amide transition state. Evidence included secondary deuterium isotope effects, molecular modeling, mutagenesis, and bound inhibitor structure. We anticipated that the ketones would be poor 
inhibitors, while the reduced amides, as twisted-amide analogues, would fare better. Indeed, the reduced amide 3 is a better Pin1 inhibitor than a similarly substituted substrate analogue -alkene isostere 5. Our crystal structure of reduced amide 4 bound to the Pin1 catalytic site adopted a trans-pyrrolidine conformation, supporting the twisted-amide mechanism. Ketones have been widely used as analogues of aldehydes or carboxylic acids to inhibit serine, cysteine, and aspartyl proteases. Substrate-analogue ketones have not yet been Dabrafenib developed as inhibitors of Pin1. Juglone is a ketone natural product that was shown to be a non-specific inhibitor of Pin1 through Michael addition to a surface Cys thiol of Pin1, resulting in unfolding. Daum et al developed a series of aryl indanyl ketone inhibitors of Pin1; the best inhibitor had an IC50 value of 0.2 mM. These inhibitors were reversible and cell penetrating, and they showed biological activities against p53 and b-catenin. Daum et al proposed that the aryl indanyl ketones mimic the transition state of the twisted amide, based on the conformation in a crystal structure. a-Ketoamides 6a and 6b were designed as potential transition state analogue inhibitors of Pin1, but their weak inhibition could not be used support either the twisted-amide or the nucleophilic-addition mechanism. As important targets for b-lactams and against the background of increasing clinical resistance to existing antibiotics, much effort has been directed toward developing new inhibitors of PBPs. Some approaches have sought to adapt the b-lactam moiety by, for instance, incorporating elements of the peptide substrates onto one of the R1 or R2 side chains, while others have synthesized compounds that mimic the tetrahedral intermediates of the reaction, including phosphonates and boronates.