Journal ArticleDOI
Cyclic peptide engineered from phytocystatin inhibitory hairpin loop as an effective modulator of falcipains and potent antimalarial
Manasi Mishra,Vigyasa Singh,Meenakshi B. Tellis,Rakesh Joshi,Rakesh Joshi,Kailash C. Pandey,Shailja Singh,Shailja Singh +7 more
TLDR
Results indicated that cyclization can substantially increase the peptide affinity to the target and this can be applied as an effective strategy for engineering peptide inhibitory potency against proteases.Abstract:
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.read more
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Identifying structural-functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation.
Priyashi Rao,Rohit Patel,Arpit Shukla,Paritosh Parmar,Rakesh Rawal,Meenu Saraf,Dweipayan Goswami +6 more
TL;DR: Molecular dynamics simulation showed Fonsecin to interact with Tyr268 of SARS-CoV2-PLpro more efficiently than control (GRL0617) and interacting with a greater number of amino acids in the binding cleft of PLpro.
Journal ArticleDOI
iAMAP-SCM: A Novel Computational Tool for Large-Scale Identification of Antimalarial Peptides Using Estimated Propensity Scores of Dipeptides
Phasit Charoenkwan,Nalini Schaduangrat,Pietro Liò,Mohammad Ali Moni,Pramote Chumnanpuen,Watshara Shoombuatong +5 more
TL;DR: The iAMAP-SCM as mentioned in this paper was proposed for the large-scale identification and characterization of peptides with antimalarial activity by using only sequence information and employed an interpretable scoring card method (SCM) to estimate propensities of 20 amino acids and 400 dipeptides to be AMAPs.
Journal ArticleDOI
Bioactive Peptides against Human Apicomplexan Parasites
Norma Rivera-Fernández,Jhony Anacleto-Santos,Brenda Casarrubias-Tabarez,Teresa de Jesús López-Pérez,Marcela Rojas-Lemus,Nelly López-Valdez,Teresa I. Fortoul +6 more
TL;DR: A review of the experimental effects of bioactive peptides on Apicomplexan parasites is presented in this article , along with comments on the mechanisms of action of peptide-based drugs.
Journal ArticleDOI
Screening of potential antiplasmodial agents targeting cysteine protease-Falcipain 2: a computational pipeline.
Kanika Verma,A. K. Lahariya,Garima Verma,Monika Kumari,Diva Gupta,Neha Maurya,Anil Kumar Verma,Ashutosh Mani,Kristan A. Schneider,Praveen K. Bharti +9 more
TL;DR: The screening of approved drugs listed in DrugBank is reported using a computational pipeline that includes drug-likeness, toxicity assessments, oral toxicity evaluation, oral bioavailability, docking analysis, maximum common substructure (MCS) and molecular dynamics (MD) Simulations analysis to identify capable FP2 inhibitors, which are hence potential antiplasmodial agents.
Journal ArticleDOI
Characterization of a novel cysteine protease inhibitor in Baylisascaris schroederi migratory larvae and its role in regulating mice immune cell response
TL;DR: It is preliminarily confirmed that rBsCPI-1 affects the physiological activities and polarization of MDMs through the TLR2/4 signaling pathway, and further interferes with antigen presentation response, inducing CD4+ T cells to play an immunosuppressive cellular response during the migratory process of B. schroederi.
References
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Journal ArticleDOI
The Future of Peptide‐based Drugs
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