Delivery of Small Molecules by Syndiotactic Peptides for Breast Cancer Therapy.

The utilization of peptide-based drug delivery systems has been suboptimal due to their poor proteolytic susceptibility, poor cell permeability, and limited tumor homing capabilities. Earlier attempts in using d-enantiomers in peptide sequences increased proteolytic stability but have compromised the overall penetration capability. We designed a series of peptides (STRAPs) with a syndiotactic polypeptide backbone that can potentially form a spatial array of cationic groups, an important feature that facilitates cellular uptake.

Molecular hybridization combining tumor homing and penetrating peptide domains for cellular targeting.

A complete peptide-based drug delivery unit has been designed with a tumor homing domain chemically linked to a syndiotactic cell-penetrating domain. The designed peptides were synthesized, characterized, and tested in vitro for cellular uptake and cytotoxicity evaluation. The differential uptake, cellular internalization, negligible hemotoxicity, selective toxicity to MDA-MB-231 breast cancer cells, and the superior penetration in three-dimensional MDA-MB-231 tumorospheres confirm their utility as a promising delivery vector.

Peptide-based delivery vectors with pre-defined geometrical locks.

Design of peptide-based targeted delivery vectors with attributes of specificity and selective cellular targeting by fixing their topology and resulting electrostatic fingerprint is the objective of this study. We formulated our peptide design platform by utilizing the possibilities of side-chain induced geometric restrictions in a typical peptide molecule. Conceptually, we locked the conformation of the RGD/NGR motif of tumor homing peptides (THPs) by mutating glycine in these motifs with d-proline and tailed the peptides with a syndiotactic amphipathic segment for cellular penetration.

Geometry encoded functional programming of tumor homing peptides for targeted drug delivery.

Poly-peptide molecules have shown promising applications in drug delivery and tumor targeting. A series of tumor homing peptides were designed by exhaustively sampling low energy geometrical basins of amino acids at specific sites of a peptide molecule to induce a conformational lock. This peptide library was pruned to a limited set of eight molecules, employing electrostatic interactions, docking, and molecular dynamics simulations.

Mapping drug-target interactions and synergy in multi-molecular therapeutics for pressure-overload cardiac hypertrophy.

Advancements in systems biology have resulted in the development of network pharmacology, leading to a paradigm shift from "one-target, one-drug" to "target-network, multi-component therapeutics". We employ a chimeric approach involving in-vivo assays, gene expression analysis, cheminformatics, and network biology to deduce the regulatory actions of a multi-constituent Ayurvedic concoction, Amalaki Rasayana (AR) in animal models for its effect in pressure-overload cardiac hypertrophy. The proteomics analysis of in-vivo assays for Aorta Constricted and Biologically Aged rat models identify proteins expressed under each condition.

Conformationally constrained peptides for drug delivery.

Peptides have shown great potential in acting as template for developing versatile carrier platforms in nanomedicine, aimed at selective delivery of drugs to only pathological tissues saving its normal neighbors. Cell-penetrating peptides (CPPs) are short oligomeric peptides capable of translocating across the cell membrane while simultaneously employing multiple mechanisms of entry. Most CPPs exist as disordered structures in solution and may adopt a helical conformation on interaction with cell membrane, vital to their penetrative capability.

Topological effects on the designability and bactericidal potency of antimicrobial peptides.

New ideas and methods are being developed to generate highly designable small functional protein folds beyond the confines of natural structures, from secondary to quaternary level. Highly designable folds can have multiple sequence solutions, which are thermodynamically and kinetically stable. We have previously described how short syndiotactic helices can be exceptionally stable energetically, and how they can be used as a template for designing antibacterial agents.

Syndiotactic peptides for targeted delivery.

Lack of cell-type specificity and proteolytic susceptibility have long been the major bottlenecks for the development of peptide-based biomaterials for targeted drug delivery. Though a poly-l backbone provides the adaptability to re-conform the peptide structure to bind to a receptor, it also makes the peptide more susceptible to proteolytic cleavage. We have attempted to address this issue by designing a set of syndiotactic peptides de novo, with alternating l- and d-amino acids in succession.

Effect of tacticity-derived topological constraints in bactericidal peptides.

Topology is a key element in structure-activity relationship estimation while designing physiologically-active molecular constructs. Peptides may be a preferred choice for therapeutics, principally due to their biocompatibility, low toxicity and predictable metabolism. Peptide design only guarantees functional group constitution by opting specific amino acid sequence, and not their spatial orientation to bind and incite physiological response on chosen targets.

Mapping the Geometric Evolution of Protein Folding Motor.

Polypeptide chain has an invariant main-chain and a variant side-chain sequence. How the side-chain sequence determines fold in terms of its chemical constitution has been scrutinized extensively and verified periodically. However, a focussed investigation on the directive effect of side-chain geometry may provide important insights supplementing existing algorithms in mapping the geometrical evolution of protein chains and its structural preferences.

bPE toolkit: toolkit for computational protein engineering.

We present a computational toolkit consisting of five utility tools, for performing basic operations on a protein structure file in PDB format. The toolkit consists of five different programs which can be integrated as part of a pipeline for computational protein structure characterization or as a standalone analysis package. The programs include tools for chirality check for amino acids (ProChiral), contact map generation (CoMa), data redundancy (DaRe), hydrogen bond potential energy (HyPE) and electrostatic interaction energy (EsInE).

Characterization of ICAM-1 biophore to design cytoadherence blocking peptides.

Peptides from natural sources are good starting material to design bioactive agents with desired therapeutic property. IB peptide derived from the ICAM-1 has been studied extensively as an agent to disrupt the non-specific binding of lymphocyte to the endothelial cells. ICAM-1: IB molecular model reveals that IB peptide binds in an extended conformation to the ICAM-1, masking LFA-1 and partially covering PfEMP-1 binding site.

Structure-based barcoding of proteins.

A reduced representation in the format of a barcode has been developed to provide an overview of the topological nature of a given protein structure from 3D coordinate file. The molecular structure of a protein coordinate file from Protein Data Bank is first expressed in terms of an alpha-numero code and further converted to a barcode image. The barcode representation can be used to compare and contrast different proteins based on their structure.