02420nas a2200265   4500008004100000245011300041210006900154260000800223300000600231490000700237520156200244653001401806653003101820653001401851653001301865653001301878653001101891653002401902100001901926700001901945700002601964700002201990700001902012856012302031       2021                        eng d00aRepurposing the McoTI-II rigid molecular scaffold in to inhibitor of `papain superfamily' cysteine proteases0 aRepurposing the McoTIII rigid molecular scaffold in to inhibitor  cJAN  a70 v143 a<p>Clan C1A or `papain superfamily' cysteine proteases are key players in many important physiological processes and diseases in most living systems. Novel approaches towards the development of their inhibitors can open new avenues in translational medicine. Here, we report a novel design of a re-engineered chimera inhibitor Mco-cysteine protease inhibitor (CPI) to inhibit the activity of C1A cysteine proteases. This was accomplished by grafting the cystatin first hairpin loop conserved motif (QVVAG) onto loop 1 of the ultrastable cyclic peptide scaffold McoTI-II. The recombinantly expressed Mco-CPI protein was able to bind with micromolar affinity to papain and showed remarkable thermostability owing to the formation of multi-disulphide bonds. Using an in silico approach based on homology modelling, protein-protein docking, the calculation of the free-energy of binding, the mechanism of inhibition of Mco-CPI against representative C1A cysteine proteases (papain and cathepsin L) was validated. Furthermore, molecular dynamics simulation of the Mco-CPI-papain complex validated the interaction as stable. To conclude, in this McoTI-II analogue, the specificity had been successfully redirected towards C1A cysteine proteases while retaining the moderate affinity. The outcomes of this study pave the way for further modifications of the Mco-CPI design for realizing its full potential in therapeutics. This study also demonstrates the relevance of ultrastable peptide-based scaffolds for the development of novel inhibitors via grafting.</p>
10aCathepsin10aClan CA cysteine proteases10acyclotide10acystatin10aMcoTI-II10apapain10aprotein engineering1 aMishra, Manasi1 aSingh, Vigyasa1 aTellis, Meenakshi, B.1 aJoshi, Rakesh, S.1 aSingh, Shailja  uhttps://library.ncl.res.in/content/repurposing-mcoti-ii-rigid-molecular-scaffold-inhibitor-papain-superfamily-cysteine02364nas a2200229   4500008004100000022001400041245008700055210006900142260000900211300001200220490000700232520163500239653001201874653002301886653002501909653001101934653001401945100002601959700002401985700002202009856010302031       2023                        eng d  a0959-665800aRegulation of trehalose metabolism in insects: from genes to the metabolite window0 aRegulation of trehalose metabolism in insects from genes to the   cMAY   a262-2730 v333 a<p>
	Trehalose is a major circulatory sugar in the haemolymph of insects. It provides instant energy and protection against stress. Trehalose metabolism is associated with insect growth and development. The architecture and spatio-temporal expression dynamics of trehalose metabolism and transport genes are key for regulation. These genes are controlled by various transcription factors, largely linked to nutrition, insect development, and metamorphosis. Also, trehalose levels are affected by substrate affinities and modifications of enzymes involved in the pathway. A feedback mechanism involving the precursors and products can regulate trehalose metabolism. Further, the neuroendocrine system controls trehalose levels under normal and stressed conditions by producing different hormones. Hypotrehalosemic hormones work under surplus energy conditions to activate haemolymph trehalose uptake and degradation. In contrast, hypertrehalosemic hormones stimulate trehalose production in the fat body and its transport to the haemolymph. However, trehalose metabolism regulation in insects needs to be studied in detail. This review discusses aspects of trehalose synthesis, transport, and degradation dynamics in developmental transition and stress response. Unraveling the epigenetic factors, transcriptional control and chemical or genetic modulators can provide further insights into the intricate regulation of trehalose in a development- and tissue-specific manner. This molecular information about effectors and regulators of trehalose metabolism can be applied in developing diverse biotechnological applications.</p>
10aHormone10aInsect development10aMetabolic regulation10aStress10atrehalose1 aTellis, Meenakshi, B.1 aKotkar, Hemlata, M.1 aJoshi, Rakesh, S.  uhttps://library.ncl.res.in/content/regulation-trehalose-metabolism-insects-genes-metabolite-window