Komal Sharma
Life Science Rsch Prof 1, Structural Biology
All Publications
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Visualizing cortical blood perfusion after photothrombotic stroke in vivo by needle-shaped beam optical coherence tomography angiography
PHOTONIX
2024; 5 (1)
View details for DOI 10.1186/s43074-024-00124-9
View details for Web of Science ID 001195142600001
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Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.
Medicinal research reviews
2023; 43 (4): 775-828
Abstract
Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.
View details for DOI 10.1002/med.21936
View details for PubMedID 36710510
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Synthetic amino acids-based short amphipathic peptides exhibit antifungal activity by targeting cell membrane disruption.
Drug development research
2023; 84 (3): 514-526
Abstract
Availability of a limited number of antifungal drugs created a necessity to develop new antifungals with distinct mode of action. Investigation on a new series of peptides led us to identify Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor exhibiting IC50 value of 4.4 µg/mL against Cryptococcus neoformans. Analog 10g exhibit high selectivity to fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. 10g produced fungicidal effect on growing cryptococcal cells and displayed synergistic effect with amphotericin B. Overall cationic character of 10g resulted in interaction with negatively charged fungal membrane while hydrophobicity enhanced penetration inside the cryptococcal cells causing hole(s) formation and disruption to the membrane as evident by the scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy analyses. Flow cytometric investigation revealed rapid death of fungal cells by apopotic pathway.
View details for DOI 10.1002/ddr.22041
View details for PubMedID 36757096
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Anticryptococcal activity and mechanistic studies of short amphipathic peptides.
Archiv der Pharmazie
2023; 356 (4): e2200576
Abstract
Cryptococcus neoformans, an opportunistic fungal pathogen, causes cryptococcosis in immunocompromised persons. A series of modified L-histidines-containing peptides are synthesized that exhibit promising activity against C. neoformans. Analog 11d [L-His(2-adamantyl)-L-Trp-L-His(2-phenyl)-OMe] produced potency with an IC50 of 3.02 µg/ml (MIC = 5.49 µg/ml). This peptide is noncytotoxic and nonhaemolytic at the MIC and displays synergistic effects with amphotericin B at subinhibitory concentration. Mechanistic investigation of 11d using microscopic tools indicates cell wall and membrane disruption of C. neoformans, while flow cytometric analysis confirms cell death by apoptosis. This study indicates that 11d exhibits antifungal potential and acts via the rapid onset of action.
View details for DOI 10.1002/ardp.202200576
View details for PubMedID 36592413
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Peptide-based drug discovery: Current status and recent advances.
Drug discovery today
2023; 28 (2): 103464
Abstract
The progressive development of peptides from reaction vessels to life-saving drugs via rigorous preclinical and clinical assessments is fascinating. Peptide therapeutics have gained momentum with the evolution of techniques in peptide chemistry, such as microwave irradiation in solid- and solution-phase synthesis, ligation chemistry, recombinant synthesis, and amalgamation with synthetic tools, including metal catalysis. Diverse emerging technologies, such as DNA-encoded libraries (DELs) and display techniques, are changing the status quo in the discovery of peptide therapeutics. In this review, we analyzed US Food and Drug Administration (FDA)-approved peptide drugs and those in clinical trials, highlighting recent advances in peptide-based drug discovery.
View details for DOI 10.1016/j.drudis.2022.103464
View details for PubMedID 36481586
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Synthetic amino acids-derived peptides target Cryptococcus neoformans by inducing cell membrane disruption.
Bioorganic chemistry
2023; 130: 106252
Abstract
We investigated synthetic amino acid-based approach to design short peptide-based antibiotics. Tautomerically restricted, amphiphilic 1-aryl-l-histidines along with hydrophobic tryptophan were utilized to synthesize the designed peptides. l-Trp-l-His(1-biphenyl)-NHBzl (12e, IC50 = 1.91 μg/mL; MIC = 3.46 μg/mL) and l-His[1-(4-n-butylphenyl)]-l-Trp-l-His[1-(4-n-butylphenyl)]-NHBzl (16d, IC50 = 1.36 μg/mL; MIC = 2.46 μg/mL) produced potency against Cryptococcus neoformans. Peptides with moderate antibacterial activities (IC50s = 4.40-8.80 μg/mL) were also identified. The mechanism of action and cellular changes revealed that membrane disruption due to interactions of the positively charged peptides with the negatively charged membrane of the cryptococcal cells result in permeabilization, leading to pore formation. The internal localization of the peptides instigated the interactions with DNA causing fragmentation of the genetic material, which together with membrane disruption led to cell death. Flow cytometric analysis points to cells death by apoptotic pathway. Time kill kinetics and synergistic study confirmed the fungicidal nature and synergism with amphotericin B.
View details for DOI 10.1016/j.bioorg.2022.106252
View details for PubMedID 36379149
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Ring-Modified Histidine-Containing Cationic Short Peptides Exhibit Anticryptococcal Activity by Cellular Disruption.
Molecules (Basel, Switzerland)
2022; 28 (1)
Abstract
Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short cationic peptides exhibiting anticryptococcal activity via membrane lysis. The N-1 position of histidine was benzylated, followed by iodination at the C-5 position via electrophilic iodination, and the dipeptides were obtained after coupling with tryptophan. In vitro analysis revealed that peptides Trp-His[1-(3,5-di-tert-butylbenzyl)-5-iodo]-OMe (10d, IC50 = 2.20 μg/mL; MIC = 4.01 μg/mL) and Trp-His[1-(2-iodophenyl)-5-iodo)]-OMe (10o, IC50 = 2.52 μg/mL; MIC = 4.59 μg/mL) exhibit promising antifungal activities against C. neoformans. When administered in combination with standard drug amphotericin B (Amp B), a significant synergism was observed, with 4- to 16-fold increase in the potencies of both peptides and Amp B. Electron microscopy analysis with SEM and TEM showed that the dipeptides primarily act via membrane disruption, leading to pore formation and causing cell lysis. After entering the cells, the peptides interact with the intracellular components as demonstrated by confocal laser scanning microscopy (CLSM).
View details for DOI 10.3390/molecules28010087
View details for PubMedID 36615282
View details for PubMedCentralID PMC9821961
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Anticryptococcal activity and mechanistic investigation of histidine-rich short peptides
JOURNAL OF MOLECULAR STRUCTURE
2023; 1276
View details for DOI 10.1016/j.molstruc.2022.134813
View details for Web of Science ID 000904118100002
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Antifungal evaluation and mechanistic investigations of membrane active short synthetic peptides-based amphiphiles.
Bioorganic chemistry
2022; 127: 106002
Abstract
The quest for new class of peptide-based antibiotics has steered this research towards the design and synthesis of short sequences possessing modified amphiphilic histidine along with hydrophobic tryptophan residues. The new structural class of dipeptides Trp-His(1-Bn)-OMe/NHBn and tripeptides His(1-Bn)-Trp-His(1-Bn)-OMe/NHBn demonstrated promising antifungal and antibacterial activities with membrane lytic action. The illustration of desirable hydrophilic-lipophilic balance appeared in the dipeptide Trp-His[1-(3,5-di-tert-butylbenzyl)]-NHBn (13d) that produced the most promising antifungal activity with IC50 value of 2.10 μg/mL and MIC = 3.81 μg/mL against C. neoformans and antibacterial activity against E. faecalis and S. aureus with identical IC50 value of 4.40 μg/mL and MIC of 8.0 μg/mL. Peptide 13d did not exhibit cytotoxicity and hemolysis at the MIC value and above. This quintessence amphiphilicity was further corroborated by the mechanistic elucidations, which revealed that, peptide act by utilizing charge and hydrophobicity as the primary characteristic tools. Owing to their fundamental affinity, the negatively charged fungal membrane is enacted upon by the positively charged peptide, whereas the intrinsic hydrophobicity of the peptide allowed penetration into the lipophillic core of the fungal cell membrane. Consequently, the integrity of cell membrane is compromised leading to increased fluidity. The membrane eventually disintegrates thereby creating a hollow pore and appearance of a doughnut into the cell when visualized under SEM. The cell death mechanism and damage to the cell wall and intracellular organelles have been elucidated with the help of flow cytometry, TEM and CLSM studies.
View details for DOI 10.1016/j.bioorg.2022.106002
View details for PubMedID 35816873
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Peptide-Heterocycle Conjugates as Antifungals Against Cryptococcosis
ASIAN JOURNAL OF ORGANIC CHEMISTRY
2022; 11 (7)
View details for DOI 10.1002/ajoc.202200196
View details for Web of Science ID 000815027000001
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β-Carbolines as potential anticancer agents.
European journal of medicinal chemistry
2021; 216: 113321
Abstract
β-Carbolines are indole alkaloids having a tricyclic pyrido[3,4-b]indole ring in their structure. Since the isolation of first β-carboline from Peganum harmala in 1841, the isolation and synthesis of various β-carboline derivatives surged in the following centuries. β-Carboline derivatives due to their widespread availability from natural sources, structural flexibility, quick reactivity and interaction with varied anticancer targets such as DNA (intercalation, groove binding, etc.), enzymes (GPX4, topoisomerases, kinases, etc.) and proteins (tubulin, ABCG2/BRCP1, etc.) have established themselves as promising lead compounds for the synthesis of various anticancer active agents. The current review covers the synthesis and isolation, anticancer activity, mechanism of action and SAR of various β-carboline containing molecules, its derivatives and congeners.
View details for DOI 10.1016/j.ejmech.2021.113321
View details for PubMedID 33684825
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Supramolecular gels from sugar-linked triazole amphiphiles for drug entrapment and release for topical application.
RSC advances
2019; 9 (34): 19819-19827
Abstract
A simple molecular framework obtained by cross-linking a hydrophobic chain with S,S- and R,R-tetritol by the copper-catalysed azide-alkyne cycloaddition reaction is found to serve as an excellent bioisostere for self-assembly. The hexadecyl-linked triazolyl tetritol composite spontaneously self-assembles in n-hepane and methanol to form hierarchical organogels. Microscopic analyses and X-ray diffraction studies demonstrate eventual formation of nanotubes through lamellar assembly of the amphiphiles. A rheological investigation shows solvent-dictated mechanical properties that obey power law behavior similar to other low molecular weight gelators (LMOGs). The gel network was then utilized for the entrapment of drugs e.g. ibuprofen and 5-fluorouracil, with tunable mechanical behaviour under applied stress. The differential release profiles of the drugs over a period of a few hours as a result of the relative spatio-temporal location in the supramolecular network can be utilized for topical formulations.
View details for DOI 10.1039/c9ra02868d
View details for PubMedID 35519397
View details for PubMedCentralID PMC9065371
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Short Antimicrobial Peptides.
Recent patents on anti-infective drug discovery
2018; 13 (1): 12-52
Abstract
After the era of serendipitous discovery of penicillin and outburst in the discovery and development of highly efficient antibiotics, a surge in resistance against the target specific drugs was observed, primarily due to a combination of selective pressure of antibiotics use and spontaneous mutations. As per the World Health Organization, antibiotic resistance is one of the greatest threats to the mankind.Short antimicrobial peptides (SAMPs) can be considered as a viable therapeutic alternative to conventional antibiotics in tackling resistant microbes. The ubiquitous nature of SAMPs combined with their ability to act via non-specific modes of action, high activity against a wide spectrum of drug-sensitive and drug-resistant microbes, and relative insusceptibility against the development of resistance adds to their desirability as new generation antibiotics.Due to the natural tendency of peptides to get metabolized by proteolytic enzymes, modification of naturally occurring SAMPs is desirable. The modifications can be done either by incorporating unnatural or modified amino acids into the peptide chain or by protecting C and N termini. The characteristic feature of SAMPs is their hydrophobicity and cationicity, which aid in the effective killing of microbes by selectively binding target and lysing the microbial cells with less deleterious effects on the host cells as compared to AMPs and other conventional antibiotics.Herein, we discussed the arsenal of short peptides and peptidomimetics starting from the smallest unit possible - a dipeptide to a decapeptide along with their activity profiles as antimicrobials. Recently, various SAMPs have paved their ways from in vitro studies to clinical trials, as evident from the most recent patent (EP1951194) on oral hygiene. This step by step growth of SAMPs has restored the hope in peptide-based therapeutics, which may prove an essential tool in eradicating antimicrobial resistance and tackling various microbial infections.
View details for DOI 10.2174/1574891X13666180628105928
View details for PubMedID 29952266