Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics.

Aberrant expression of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been associated with the incidence of many diseases, particularly cancer, and it has evolved as a promising epigenetic target over the years for treatment. The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat). There is parallel mining for peptide-based LSD1 inhibitors, which exploits the opportunities in the LSD1 substrate binding pocket. This Review highlights the research progress on reversible and irreversible peptide/peptide-derived LSD1 inhibitors. For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

Reactive oxygen species-responsive thymine-conjugated chitosan: Synthesis and evaluation as cryogel.

Chitosan (CS) is a biodegradable, biocompatible cationic polysaccharide based natural polymer with antibacterial and anti-inflammatory properties. Hydrogels made from CS have found their applications in wound healing, tissue regeneration and drug delivery. Although, mucoadhesive properties are resulted from the polycationic nature of CS, in hydrogel form amines are engaged in interactions with water leading to decrease in mucoadhesive properties. In case of injury, presence of elevated level of reactive oxygen species (ROS) has inspired many drug delivery platforms to conjugate ROS responsive linkers for on demand drug delivery. In this report we have conjugated a reactive oxygen species (ROS) responsive thioketal (Tk) linker and nucleobase thymine (Thy) with CS. Cryogel from this doubly functionalized polymer CS-Thy-Tk was prepared through crosslinking with sodium alginate. Inosine was loaded on the scaffold and studied for its release under oxidative condition. We anticipated that the presence of thymine shall retain the mucoadhesive nature of the CS-Thy-Tk polymer in hydrogel form and when placed at the site of injury, due to the presence of excessive ROS at inflammatory condition, loaded drug shall release due to degradation of the linker. Porous cryogel scaffold was prepared via chemical crosslinking of amine functional group of chitosan with carboxylic acid containing polysaccharide sodium alginate. The cryogel was evaluated for porosity (FE-SEM), rheology, swelling, degradation, mucoadhesive properties and biocompatibility. Resulted scaffold was found to be porous with average pore size of 107 ± 23 µm, biocompatible, hemocompatible and possesses improved mucoadhesive property (mucin binding efficiency of 19.54 %) which was found to be 4 times better as compared to chitosan (4.53 %). The cumulative drug release found to be better in the presence of H2O2 (∼90 %) when compared to that of PBS alone (∼60-70 %). Therefore, the modified CS-Thy-TK polymer may hold potential as interesting scaffold in case of conditions associated with elevated ROS level such as injury and tumor.

Peptide Engraftment on PEGylated Nanoliposomes for Bone Specific Delivery of PTH (1-34) in Osteoporosis.

Bone-specific functionalization strategies on liposomes are promising approaches to delivering the drug in osteoporotic conditions. This approach delivers the drug to the bone surface specifically, reduces the dose and off-target effects of the drug, and thereby reduces the toxicity of the drug. The purpose of the current research work was to fabricate the bone-specific peptide conjugated pegylated nanoliposomes to deliver anabolic drug and its physicochemical evaluations. For this, a bone-specific peptide (SDSSD) was synthesized, and the synthesized peptide was conjugated with a linker (DSPE-PEG2000-COOH) to obtain a bone-specific conjugate (SDSSD-DSPE). Purified SDSSD-DSPE was characterized by HPLC, Maldi-TOF, NMR, and Scanning Electron Microscope/Energy Dispersive Spectroscopy (SEM/EDS). Further, peptide-conjugated and anabolic drug-encapsulated liposomes (SDSSD-LPs) were developed using the ethanol injection method and optimized by Central Composite Design (CCD) using a statistical approach. Optimized SDSSD-LPs were evaluated for their physicochemical properties, including surface morphology, particle size, zeta potential, in vitro drug release, and bone mineral binding potential. The obtained results from these studies demonstrated that SDSSD-DSPE conjugate and SDSSD-LPs were optimized successfully. The particle size, % EE, and zeta potential of SDSSD-LPs were observed to be 183.07 ± 0.85 nm, 66.72 ± 4.22%, and -25.03 ± 0.21 mV, respectively. SDSSD-LPs demonstrated a sustained drug release profile. Further, the in vitro bone mineral binding assay demonstrated that SDSSD-LPs deliver the drug to the bone surface specifically. These results suggested that SDSSD-LPs could be a potential targeting approach to deliver the anabolic drug in osteoporotic conditions.

Synthesis and Investigation of Backbone Modified Squaramide Dipeptide Self-Assembly.

Dipeptides are minimalistic peptide building blocks that form well ordered structures through molecular self-assembly. The driving forces involved are cooperative noncovalent interactions such as π-π stacking, hydrogen bonding, and ionic as well as hydrophobic interactions. One of the most intriguing self-assembled motifs that has been extensively explored as a low molecular weight hydrogel for drug delivery, tissue engineering, imaging and techtonics, etc. is Phe-Phe (FF). The backbone of the dipeptide is very crucial for extending secondary structures in self-assembly, and any subtle change in the backbone drastically affect the molecular recognitions. The squaramide (SQ) motif has the unique advantage of hydrogen bonding which can promote the self-assembly process. In this work we have integrated the SQ unit into the dipeptide FF backbone to achieve molecular self-assembly. The resulting carbamate protected backbone modified dipeptide (BocFSAF-OH, 10) has exhibited molecular self-assembly with a fibrilar network. It formed a stable hydrogel (with CAC of 0.024 ± 0.0098 wt %) via the solvent switch method and was found to possess excellent enzymatic stability. The dipeptide and the resulting hydrogel were found to be cytocompatible. When integrated with a polysaccharide based biopolymer, e.g. sodium alginate, the resulting matrix exhibited strong hydrogel character. Therefore, the dipeptide hydrogel of 10 may find its applications in a variety of fields including drug delivery and tissue engineering.

Design, synthesis and in-vitro evaluation of fluorinated triazoles as multi-target directed ligands for Alzheimer disease.

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid ß aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid ß aggregation (IC50 of 4.6 µM) through selective binding with Amyloid ß at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.

Peptide-Chitosan Engineered Scaffolds for Biomedical Applications.

Peptides are signaling epitopes that control many vital biological events. Increased specificity, synthetic feasibility with concomitant lack of toxicity, and immunogenicity make this emerging class of biomolecules suitable for different applications including therapeutics, diagnostics, and biomedical engineering. Further, chitosan, a naturally occurring linear polymer composed of d-glucosamine and N-acetyl-d-glucosamine units, possesses anti-microbial, muco-adhesive, and hemostatic properties along with excellent biocompatibility. As a result, chitosan finds application in drug/gene delivery, tissue engineering, and bioimaging. Despite these applications, chitosan demonstrates limited cell adhesion and lacks biosignaling. Therefore, peptide-chitosan hybrids have emerged as a new class of biomaterial with improved biosignaling properties and cell adhesion properties. As a result, recent studies encompass increased application of peptide-chitosan hybrids as composites or conjugates in drug delivery, cell therapy, and tissue engineering and as anti-microbial material. This review discusses the recent investigations involving chitosan-peptide materials and uncovers various aspects of these interesting hybrid materials for biomedical applications.

Ultrashort Peptides-A Glimpse into the Structural Modifications and Their Applications as Biomaterials.

Because of their commanding properties, ultrashort and short peptides are gaining significance as viable candidates for molecular self-assembly, which is a naturally inspired approach for developing supramolecular structures and can be used to design various strategies of significance in the field of biomaterials. Self-assembly of biomolecules like proteins, lipids, and nucleic acids is observed in living organisms, various biological-process-based examples like amyloid-ß plaque formation, lipid bilayer assembly, and the complementary binding of the nucleotide bases of nucleic acids involve self-assembly. Among all biomolecules, peptide-based self-assembly has the advantage of the availability of the source, peptides can be easily synthesized or obtained from the natural degradation process and can be engineered to modulate their action, making them an area of immense interest for research. Multiple modification options provide a wide area for the engineering of amino acid sequences. Understanding of the amino acid residues with their existing properties and modified properties is very helpful for further improvements. Computational approaches like molecular dynamics simulations provide atomistic-level insight into the self-assembly process, by which newer physical-chemical modifications can be planned. Virtual screening of the peptides on the basis of their properties and probability for the desired activity are helpful as well. Engineered and programmed peptides have been reported for various applications like drug delivery and target specific formulations. A combined approach of computational and experimental studies is helpful to understand and optimize the self-assembly process and mechanism at the atomic level. These self-assembled ultrashort peptides have been used in a wide range of applications from hydrogels to drug delivery agents, biosensors, emulsifiers, and so on.

Rh(III)-Catalyzed [3 + 2] Annulation via C-H Activation: Direct Access to Trifluoromethyl-Substituted Indenamines and Aminoindanes.

The rhodium(III)-catalyzed direct C-H addition and annulation of benzimidates and aldimines with ß-(trifluoromethyl)-α,ß-unsaturated ketones is described. This protocol provides the facile and efficient formation of various trifluoromethyl-containing indenamines or aminoindanes in moderate to high yields.