02795nas a2200265   4500008004100000022001400041245014500055210006900200260000800269300001400277490000900291520187200300653001902172653001602191653001702207653002302224653001802247100002702265700002202292700002002314700002002334700002402354700002002378856013102398       2019                        eng d  a0304-416500aPhyto-inspired cyclic peptides derived from plant Pin-II type protease inhibitor reactive center loops for crop protection from insect pests0 aPhytoinspired cyclic peptides derived from plant PinII type prot  cAUG  a1254-12620 v18633 a<p>Background: Natural defence of plants against insect pests involves protease inhibitors (PIs) that interfere with insect digestive proteases. Pin-II type plant PIs are wound inducible upon insect damage and possess multiple inhibitory repeat domains that can inhibit trypsin and chymotrypsin-like proteases in the insect midgut. Yet, their agricultural ex-vivo application is limited due to large molecular size and environmental instability, which could be overcome by small peptides. Methods: Bicyclic peptides were designed by grafting Pin-II PIs derived reactive center loop (RCL) on synthetic tris(bromomethyl)benzene scaffold. In vitro binding with trypsin-like proteases was evaluated by biochemical and biophysical assays, followed by molecular dynamics simulations. In vivo effects on two major lepidopteran insect pests, Helicoverpa armigera and Spodoptera litura were studied upon feeding with peptide treated leaves. Affinity based pull down assays were used to identify target proteins in insect gut. Results: Bicyclic RCLs showed ten-fold enhanced protease inhibition compared to their linear counterparts. They exhibited feeding deterrence and growth reduction of lepidopteran insects. Bicyclic peptides predominantly interact with midgut serine proteases. Possible binding modes involve simultaneous interaction with the active site and specificity-determining residues of insect gut trypsin. Conclusion: Bicyclic peptides are potent inhibitors of serine proteases in the insect midgut. They cause feeding aversion and larval growth retardation. Bi-domain cyclic peptides interact with two sites on trypsin, leading to enhanced efficacy over linear RCL peptides. General significance: Bicyclic peptides mimic natural PIs by inhibiting insect proteases leading to growth reduction, thus, could be used as pest control molecules in agriculture.</p>
10aCyclic peptide10aLepidoptera10aPest control10aprotease inhibitor10aReactive loop1 aSailthedkar, Nidhi, S.1 aJoshi, Rakesh, S.1 aYadav, Amit, K.1 aSeal, Shubhendu1 aFernandes, Moneesha1 aGiri, Ashok, P.  uhttps://library.ncl.res.in/content/phyto-inspired-cyclic-peptides-derived-plant-pin-ii-type-protease-inhibitor-reactive-center02369nas a2200289   4500008004100000022001400041245013700055210006900192260000800261300001400269490000700283520140400290653001901694653002501713653001501738653000601753653001801759653003101777653001901808100001901827700001901846700002601865700002201891700002401913700001901937856012301956       2022                        eng d  a0739-110200aCyclic peptide engineered from phytocystatin inhibitory hairpin loop as an effective modulator of falcipains and potent antimalarial0 aCyclic peptide engineered from phytocystatin inhibitory hairpin   cMAY  a3642-36540 v403 a<p>
	Cystatins are classical competitive inhibitors of C1 family cysteine proteases (papain family). Phytocystatin superfamily shares high sequence homology and typical tertiary structure with conserved glutamine-valine-glycine (Q-X-V-X-G) loop blocking the active site of C1 proteases. Here, we develop a cysteine-bounded cyclic peptide (CYS-cIHL) and linear peptide (CYS-IHL), using the conserved inhibitory hairpin loop amino acid sequence. Using an in silico approach based on modeling, protein-peptide docking, molecular dynamics simulations and calculation of free energy of binding, we designed and validated inhibitory peptides against falcipain-2 (FP-2) and -3 (FP-3), cysteine proteases from the malarial parasite Plasmodium falciparum. Falcipains are critical hemoglobinases of P. falciparum that are validated targets for the development of antimalarial therapies. CYS-cIHL was able to bind with micromolar affinity to FP-2 and modulate its binding with its substrate, hemoglobin in in vitro and in vivo assays. CYS-cIHL could effectively block parasite growth and displayed antimalarial activity in culture assays with no cytotoxicity towards human cells. These results indicated that cyclization can substantially increase the peptide affinity to the target. Furthermore, this can be applied as an effective strategy for engineering peptide inhibitory potency against proteases.</p>
10aCyclic peptide10afalcipain inhibitors10afalciparum10aP10aPhytocystatin10aprotein interaction mimics10aprotein&\#82111 aMishra, Manasi1 aSingh, Vigyasa1 aTellis, Meenakshi, B.1 aJoshi, Rakesh, S.1 aPandey, Kailash, C.1 aSingh, Shailja  uhttps://library.ncl.res.in/content/cyclic-peptide-engineered-phytocystatin-inhibitory-hairpin-loop-effective-modulator