Big-renin

The big renin and the big-big renin were purified by the method shown in the following scheme ... 

Figure 7. Chromatographic elution pattern of porcine big-renin (BB), big renin (B) and small renin (S) from a Sephadex G-150 column. The renin preparation obtained after affinity chromatography on a pepstatin-aminobutyl-agarose gel was the starting material. The renin activity (- -) and protein concentration (—) were determined as in Figure 2 and Ref. (60). ...

Properties of these high-molecular-weight renins are summarized in Table VII. The fact that the pi of the big-big renin is clearly different from that of the other species eliminates the possibility that big-big renin is an oligomeric complex of the smaller species. The inverse relationship between the molecular weights and the specific activities of these renins strongly suggests the existence of an enzyme-precursor relationship as shown below ... 

In the context of this scheme, big-big renin I with a higher specific activity than big-big renin II may very well be another intermediate product of activation. Although big-big renin II is only 1/2,000 as active as the small renin, it is possible that a completely inactive renin precursor exists. 

Figure 9. Polyacrylamide gel electrophoresis of purified porcine big renin (B), big-big renin I (BB-I) and big-big renin II (BB-II). Ref. (60).

This observation agrees with those of Boyd (51) and of Leckie and McConnell (55). It was not possible, however, to activate pure big renin under the conditions which have been shown to activate big renin in crude systems (48,50,51,62). The observation of big-big renin in our study was the first discovery of renin of this molecular size. The existence of a renin with a very low specific activity, much lower than that of big renin, suggests the possible presence of a totally inactive, high-molecular-weight zymogen of renin. This big-big renin, however, seems to be different from the very-high-molecular-weight substance observed by Barrett et al. (58). 

The reverse flow of clinical candidates from big pharma to start-up companies is actually not that unusual many pharma companies are now willing to part with drugs they don t wish to develop for various, oftentimes business, reasons. Others besides Synosis have been born this way, for example the Swiss company Speedel which obtained clinical POC for the first-in-class renin inhibitor Tekturna (aliskiren. Figure 2.8), which was recently approved. 

Fig. 1. Effect of the concentration of a-bromoisocaproyl (BIG) peptides on the inactivation of submaxillary renin. Mouse submaidllary renin A (0.1 mg in 1 ml) was incubated with t-BIC-Val-TyrNH, (O) or n-BIC-Leu-Val-Tyr-Ser-OH ( ) in 0.04 M sodium pyrophosphate (pH 5j6) at 37° for 10 hr. The inactivators were added as solution in ethylene glycol monoethyl ether. The concentration of the organic solvent was 10% (v/v) throughout this experiment.

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