The PROTACtable genome.

Proteolysis-targeting chimeras (PROTACs) are an emerging drug modality that may offer new opportunities to circumvent some of the limitations associated with traditional small-molecule therapeutics. By analogy with the concept of the 'druggable genome', the question arises as to which potential drug targets might PROTAC-mediated protein degradation be most applicable. Here, we present a systematic approach to the assessment of the PROTAC tractability (PROTACtability) of protein targets using a series of criteria based on data and information from a diverse range of relevant publicly available resources. Our approach could support decision-making on whether or not a particular target may be amenable to modulation using a PROTAC. Using our approach, we identified 1,067 proteins of the human proteome that have not yet been described in the literature as PROTAC targets that offer potential opportunities for future PROTAC-based efforts.

Comparison of the proteome of Mycobacterium tuberculosis strain H37Rv with clinical isolate CDC 1551.

The genome sequences of two virulent strains of Mycobacterium tuberculosis (H37Rv and CDC 1551) are now available. CDC 1551 is a recent clinical isolate and H37Rv is a commonly used lab strain which has been subject to in vitro passage. The two strains have been shown to display differing phenotypes both in vivo and in vitro. The proteome of the two strains grown in liquid culture were examined over time to determine whether there are any major differences between them at the protein level and the differences were compared to the genome data. Total cell lysates of the two strains were analysed by two-dimensional electrophoresis. Approximately 1750 protein spots were visualized by silver staining and the protein profiles of the two strains were found to be highly similar. Out of a total of 17 protein spot differences, seven were unique to CDC 1551 and three to H37Rv. Two further spots showed increased intensity in H37Rv, one spot showed differing vertical mobility between the strains and four showed differing spot intensities with time. Twelve of the spot differences were identified using mass spectrometry; however, no obvious association with phenotype could be deduced. When genome differences were analysed and related to the proteome differences, a mobility shift identified in the MoxR protein could be explained by a point mutation at the gene level. This proteome analysis reveals that, despite having been maintained under vastly different conditions, namely in vitro passage and in vivo transmission, these two strains have remained highly similar.