N-tosyl-D-proline

Fig. 9.4 Improvements in potency of N-tosyl-D-proline. Structural analyses revealed that the glutamate moiety from the mTHF cofactor could be appended to the hit from Tethering, and further elaboration led to a submicromolar inhibitor.

Fig. 9.5 Structures of TS with the N-tosyl-D-proline fragment bound through two different cysteine residues (red, blue) or non-covalently bound (green). Reprinted from [12] with permission.

To learn whether the disulfide bond itself changed how the fragment binds, we determined the crystal structure of N-tosyl-D-proline bound non-covalently to TS. As shown in Fig. 9.5, the free fragment binds in a nearly identical manner to the disulfide-linked fragment, demonstrating that the covalent linkage does not affect how the fragment binds. 

In an attempt to clarify the relationship between gramicidin S and its bacterial action, Harris and Work (258,259,260) synthesized a series of noncyclic peptides structurally similar to those of the naturally occurring peptides. These peptides are as follows D-phenylalanyl-L-proline methyl ester, L-phenylalanyl-L-proline ethyl ester L-leucyl-n-phenylalanine methyl ester L-leucyl-D-phenylalanyl-L-proline methyl ester L-leueyl-L-phenylalanyl-L-proline ethyl ester L-ornithyl-L-Ieucyl-n-phenylalanyl-L-proline methyl ester a-(L-valyl)-DL-ornithyl-L-leucyl-D-phenylalanyl-L-proline methyl ester o -(L-valyl)-L-ornithyl-L-leucyl-D-phenylalanyl-L-proline a-(L(valyl)-DL-ornithyl-L-leucyl-L-phenylalanyl-L-proline ethyl ester a-(tosyl-L-valyl) -L-ornithyl-L-leucyl-n-phenylalanyl-L-proline methyl ester a-(tosyl-L-valyl)-L-ornithyl-L-leucyl-D-phenylalanyl-L-proline amide. 

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