bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–07–21
sixteen papers selected by
Henry Lamb, Queensland University of Technology
  1. Tumor microenvironment-responsive cell-penetrating peptides: Design principle and precision delivery.
  2. Heuristic energy-based cyclic peptide design.
  3. Accessing diverse bicyclic peptide conformations using 1,2,3-TBMB as a linker.
  4. Rational design of small-sized peptidomimetic inhibitors disrupting protein-protein interaction.
  5. Macrocyclic peptides derived from AcPHF6* and AcPHF6 to selectively modulate the Tau aggregation.
  6. Crafting Unnatural Peptide Macrocycles via Rh(III)-Catalyzed Carboamidation.
  7. Development of a 3D printed perfusable in vitro blood-brain barrier model for use as a scalable screening tool.
  8. Accurate Structure Prediction for Cyclic Peptides Containing Proline Residues with High-Temperature Molecular Dynamics.
  9. Facile detection of peptide-protein interactions using an electrophoretic crosslinking shift assay.
  10. Sensors for blood brain barrier on a chip.
  11. Pneumatic extrusion bioprinting-based high throughput fabrication of a melanoma 3D cell culture model for anti-cancer drug screening.
  12. Rational In Silico Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket.
  13. Preclinical evaluation of CXCR4 peptides for targeted radionuclide therapy in glioblastoma.
  14. Recent advances in methods for quantifying the cell penetration of macromolecules.
  15. Identification and Design of Novel Potential Antimicrobial Peptides Targeting Mycobacterial Protein Kinase PknB.
  16. Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.
  1. Colloids Surf B Biointerfaces. 2024 Jul 16. pii: S0927-7765(24)00359-X. [Epub ahead of print]242 114100
    Tumor microenvironment-responsive cell-penetrating peptides: Design principle and precision delivery.
    Chenhui Wang, Bo Wang, Qing Zhang, Sihe Zhang.
      Cell-penetrating peptides (CPPs) are promising vehicles for intracellular delivery of different cargoes. Although various CPPs are designed for targeted delivery of nanomedicines and anticancer drugs, their clinical approval is hampered by a lack of selectivity. In recent years, new approaches have been explored to address this drawback, and distinct strategies for tumor microenvironment (TME)-responsive activation have been developed. In this review, we first introduce the cellular uptake mechanisms of CPPs. We next extensively discuss the design principles and precision delivery of TME-responsive CPPs. Nine kinds of single stimulus-responsive CPPs, five kinds of multiple stimuli-responsive CPPs, three kinds of TME-responsive targeting CPPs, and two kinds of reversibly activatable CPPs (RACPPs) are systemically summarized. Then, TME-responsive CPPs for nanomedical applications are further discussed. Finally, we describe the translational applications of TME-responsive CPPs for anticancer drug delivery. These commentaries provide an insight into the design of next-generation activatable CPPs (ACPPs) for selective delivery of nanomedicines and anticancer drugs.
    Keywords:  Cell-penetrating peptide; Drug delivery; Reversible activation; Stimuli-responsive; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.colsurfb.2024.114100
  2. bioRxiv. 2024 Jul 04. pii: 2024.07.03.601955. [Epub ahead of print]
    Heuristic energy-based cyclic peptide design.
    Qiyao Zhu, Vikram Khipple Mulligan, Dennis E Shasha.
      Rational computational design is crucial to the pursuit of novel drugs and therapeutic agents. Meso-scale cyclic peptides, which consist of 7-40 amino acid residues, are of particular interest due to their conformational rigidity, binding specificity, degradation resistance, and potential cell permeability. Because there are few natural cyclic peptides, de novo design involving non-canonical amino acids is a potentially useful goal. Here, we develop an efficient pipeline (CyclicChamp) for cyclic peptide design. After converting the cyclic constraint into an error function, we employ a variant of simulated annealing to search for low-energy peptide backbones while maintaining peptide closure. Compared to the previous random sampling approach, which was capable of sampling conformations of cyclic peptides of up to 14 residues, our method both greatly accelerates the computation speed for sampling conformations of small macrocycles ( ca. 7 residues), and addresses the high-dimensionality challenge that large macrocycle designs often encounter. As a result, CyclicChamp makes conformational sampling tractable for 15- to 24-residue cyclic peptides, thus permitting the design of macrocycles in this size range. Microsecond-length molecular dynamics simulations on the resulting 15, 20, and 24 amino acid cyclic designs identify trajectories with kinetic stability. To test their thermodynamic stability, we perform additional replica exchange molecular dynamics simulations and generate free energy surfaces. Two 15-residue designs and one 20-residue design emerge as promising candidates, along with one viable 24-residue candidate.
    DOI:  https://doi.org/10.1101/2024.07.03.601955
  3. Org Biomol Chem. 2024 Jul 15.
    Accessing diverse bicyclic peptide conformations using 1,2,3-TBMB as a linker.
    Haritha Krishna Sudhakar, Jackie Tsz Ki Yau, Lisa J Alcock, Yu Heng Lau.
      Bicyclic peptides are a powerful modality for engaging challenging drug targets such as protein-protein interactions. Here, we use 1,2,3-tris(bromomethyl)benzene (1,2,3-TBMB) to access bicyclic peptides with diverse conformations that differ from conventional bicyclisation products formed with 1,3,5-TBMB. Bicyclisation at cysteine residues under aqueous buffer conditions proceeds efficiently, with broad substrate scope, compatibility with high-throughput screening, and clean conversion (>90%) for 96 of the 115 peptides tested. We envisage that the 1,2,3-TBMB linker will be applicable to a variety of peptide screening techniques in drug discovery.
    DOI:  https://doi.org/10.1039/d4ob00901k
  4. RSC Med Chem. 2024 Jul 17. 15(7): 2212-2225
    Rational design of small-sized peptidomimetic inhibitors disrupting protein-protein interaction.
    Junyuan Wang, Ping Zheng, Jianqiang Yu, Xiuyan Yang, Jian Zhang.
      Protein-protein interactions are fundamental to nearly all biological processes. Due to their structural flexibility, peptides have emerged as promising candidates for developing inhibitors targeting large and planar PPI interfaces. However, their limited drug-like properties pose challenges. Hence, rational modifications based on peptide structures are anticipated to expedite the innovation of peptide-based therapeutics. This review comprehensively examines the design strategies for developing small-sized peptidomimetic inhibitors targeting PPI interfaces, which predominantly encompass two primary categories: peptidomimetics with abbreviated sequences and low molecular weights and peptidomimetics mimicking secondary structural conformations. We have also meticulously detailed several instances of designing and optimizing small-sized peptidomimetics targeting PPIs, including MLL1-WDR5, PD-1/PD-L1, and Bak/Bcl-xL, among others, to elucidate the potential application prospects of these design strategies. Hopefully, this review will provide valuable insights and inspiration for the future development of PPI small-sized peptidomimetic inhibitors in pharmaceutical research endeavors.
    DOI:  https://doi.org/10.1039/d4md00202d
  5. Bioorg Chem. 2024 Jul 10. pii: S0045-2068(24)00530-3. [Epub ahead of print]151 107625
    Macrocyclic peptides derived from AcPHF6* and AcPHF6 to selectively modulate the Tau aggregation.
    Abha Dangi, Tazeen Qureshi, Subashchandrabose Chinnathambi, Udaya Kiran Marelli.
      Ten macrocyclic peptides, each comprising 14 amino acids, were designed and synthesized based on the Tau aggregation model hexapeptides AcPHF6* and AcPHF6. The design took into account the aggregation tendencies of each residue in AcPHF6* and AcPHF6, their aggregation models, while employing peptide-based structural design principles including N-methylation to promote turns and to block hydrogen bond propagation and elongation of the aggregation chain. NMR analysis supported that all these peptides adopted an antiparallel β-sheet conformation. Self-aggregation studies characterized the aggregation properties of these peptides, identifying two peptides with the highest (P3) and lowest (P8) aggregation tendencies. In cross-aggregation studies with the parent peptides AcPHF6* and AcPHF6, P3 and P8 were found to promote and reduce aggregation, respectively. Furthermore, P3 and P8 demonstrated an enhancement and diminution effect on the aggregation of K18wt, indicating their capacity to modulate aggregation even at the macromolecular level. Thus, the two simple peptides, P3 and P8 selectively exhibit pro- or anti-aggregation effects on PHF peptides and Tau. This study, has thus developed structurally well-defined non-complex peptides, derived from AcPHF6* and AcPHF6, to modulate Tau aggregation as desired, offering applications in Tau model studies and the development of Tau aggregation inhibitors or promoters.
    Keywords:  Cyclic peptides; PHF peptides; Peptide conformation; Peptide-based drug design (PBDD); Tau aggregation
    DOI:  https://doi.org/10.1016/j.bioorg.2024.107625
  6. J Am Chem Soc. 2024 Jul 18.
    Crafting Unnatural Peptide Macrocycles via Rh(III)-Catalyzed Carboamidation.
    Christopher W Lamartina, Cassandra A Chartier, Jillian M Hirano, Neel H Shah, Tomislav Rovis.
      Contemporary developments in the field of peptide macrocyclization methodology are imperative for enabling the advance of drug design in medicinal chemistry. This report discloses a Rh(III)-catalyzed macrocyclization via carboamidation, reacting acryloyl-peptide-dioxazolone precursors and arylboronic acids to form complex cyclic peptides with concomitant incorporation of noncanonical α-amino acids. The diverse and modular technology allows for expedient access to a wide variety of cyclic peptides from 4 to 15 amino acids in size and features simultaneous formation of unnatural phenylalanine and tyrosine derivatives with up to >20:1 diastereoselectivity. The reaction showcases an expansive substrate scope with 45 examples and is compatible with the majority of standard protected amino acids used in Fmoc-solid phase peptide synthesis. The methodology is applied to the synthesis of multiple peptidomimetic macrocyclic analogs, including derivatives of cyclosomatostatin and gramicidin S.
    DOI:  https://doi.org/10.1021/jacs.4c05248
  7. Biomater Sci. 2024 Jul 18.
    Development of a 3D printed perfusable in vitro blood-brain barrier model for use as a scalable screening tool.
    Madison K Royse, Martha Fowler, A Kristen Mai, Yufang He, Marc R Durante, Nicole Buist, Adam Procopio, Jun Xu, Omid Veiseh.
      Despite recent technological advances in drug discovery, the success rate for neurotherapeutics remains alarmingly low compared to treatments for other areas of the body. One of the biggest challenges for delivering therapeutics to the central nervous system (CNS) is the presence of the blood-brain barrier (BBB). In vitro blood-brain barrier models with high predictability are essential to aid in designing parameters for new therapeutics, assess their ability to cross the BBB, and investigate therapeutic strategies that can be employed to enhance transport. Here, we demonstrate the development of a 3D printable hydrogel blood-brain barrier model that mimics the cellular composition and structure of the blood-brain barrier with human brain endothelial cells lining the surface, pericytes in direct contact with the endothelial cells on the abluminal side of the endothelium, and astrocytes in the surrounding printed bulk matrix. We introduce a simple, static printed hemi-cylinder model to determine design parameters such as media selection, co-culture ratios, and cell incorporation timing in a resource-conservative and high-throughput manner. Presence of cellular adhesion junction, VE-Cadherin, efflux transporters, P-glycoprotein (P-gp) and Breast cancer resistance protein (BCRP), and receptor-mediated transporters, Transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1) were confirmed via immunostaining demonstrating the ability of this model for screening in therapeutic strategies that rely on these transport systems. Design parameters determined in the hemi-cylinder model were translated to a more complex, perfusable vessel model to demonstrate its utility for determining barrier function and assessing permeability to model therapeutic compounds. This 3D-printed blood-brain barrier model represents one of the first uses of projection stereolithography to fabricate a perfusable blood-brain barrier model, enabling the patterning of complex vessel geometries and precise arrangement of cell populations. This model demonstrates potential as a new platform to investigate the delivery of neurotherapeutic compounds and drug delivery strategies through the blood-brain barrier, providing a useful in vitro screening tool in central nervous system drug discovery and development.
    DOI:  https://doi.org/10.1039/d4bm00663a
  8. J Phys Chem B. 2024 Jul 19.
    Accurate Structure Prediction for Cyclic Peptides Containing Proline Residues with High-Temperature Molecular Dynamics.
    Botao Dai, Jia-Nan Chen, Qing Zeng, Hao Geng, Yun-Dong Wu.
      Cyclic peptides (CPs) are emerging as promising drug candidates. Numerous natural CPs and their analogs are effective therapeutics against various diseases. Notably, many of them contain peptidyl cis-prolyl bonds. Due to the high rotational barrier of peptide bonds, conventional molecular dynamics simulations struggle to effectively sample the cis/trans-isomerization of peptide bonds. Previous studies have highlighted the high accuracy of the residue-specific force field (RSFF) and the high sampling efficiency of high-temperature molecular dynamics (high-T MD). Herein, we propose a protocol that combines high-T MD with RSFF2C and a recently developed reweighting method based on probability densities for accurate structure prediction of proline-containing CPs. Our method successfully predicted 19 out of 23 CPs with the backbone rmsd < 1.0 Å compared to X-ray structures. Furthermore, we performed high-T MD and density reweighting on the sunflower trypsin inhibitor (SFTI-1)/trypsin complex to demonstrate its applicability in studying CP-complexes containing cis-prolines. Our results show that the conformation of SFTI-1 in aqueous solution is consistent with its bound conformation, potentially facilitating its binding.
    DOI:  https://doi.org/10.1021/acs.jpcb.4c02004
  9. J Biol Chem. 2024 Jul 16. pii: S0021-9258(24)02081-7. [Epub ahead of print] 107580
    Facile detection of peptide-protein interactions using an electrophoretic crosslinking shift assay.
    Benjamin W Parker, Eric L Weiss.
      Protein-protein interactions with high specificity and low affinity are functionally important but are not comprehensively understood because they are difficult to identify. Particularly intriguing are the dynamic and specific interactions between folded protein domains and short unstructured peptides known as short linear motifs (SLiMs). Such domain-motif interactions (DMIs) are often difficult to identify and study because affinities are modest to weak. Here we describe "electrophoretic crosslinking shift assay" (ECSA), a simple in vitro approach that detects transient, low affinity interactions by covalently crosslinking a prey protein and a fluorescently labeled bait. We demonstrate this technique on the well characterized DMI between MAP kinases and unstructured D-motif peptide ligands. We show that ECSA detects sequence-specific micromolar interactions using less than a microgram of input prey protein per reaction, making it ideal for verifying candidate low-affinity DMIs of components that purify with low yield. We propose ECSA as an intermediate step in SLiM characterization that bridges the gap between high throughput techniques such as phage display and more resource-intensive biophysical and structural analysis.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107580
  10. Vitam Horm. 2024 ;pii: S0083-6729(24)00021-9. [Epub ahead of print]126 219-240
    Sensors for blood brain barrier on a chip.
    Yan Liang, Jeong-Yeol Yoon.
      The blood-brain barrier (BBB) is a highly selective membrane that regulates the passage of substances between the bloodstream and the brain, thus safeguarding the central nervous system. This chapter provides an overview of current experimental models and detection methods utilized to study the BBB, along with the implementation of sensors and biosensors in BBB research. We discuss static and dynamic BBB models, highlighting their respective advantages and limitations. Additionally, we examine various detection methods employed in BBB research, including those specific to static and dynamic models. Furthermore, we explore the applications of physical sensors and biosensors in BBB models, focusing on their roles in monitoring barrier integrity and function. We also discuss recent advancements in sensor integration, such as robotic interrogators and integrated electrochemical and optical biosensors. Finally, we present a brief conclusion and future outlook, emphasizing the importance of continued innovation in BBB research to advance our understanding of neurological disorders and drug development.
    Keywords:  Biosensors; Blood-brain barrier; Detection methods; Drug development; Experimental models; In vitro models; Neurological disorders; Sensors
    DOI:  https://doi.org/10.1016/bs.vh.2024.02.006
  11. Biomed Mater. 2024 Jul 18.
    Pneumatic extrusion bioprinting-based high throughput fabrication of a melanoma 3D cell culture model for anti-cancer drug screening.
    Maryke de Villiers, Awie F Kotzé, Lissinda H du Plessis.
      The high incidence of malignant melanoma highlights the need for in vitro models that accurately represent the tumour microenvironment, enabling developments in melanoma therapy and drug screening. Despite several advancements in 3D cell culture models, appropriate melanoma models for evaluating drug efficacy are still in high demand. The 3D pneumatic extrusion-based bioprinting technology offers numerous benefits, including the ability to achieve high-throughput capabilities. However, there is a lack of research that combines pneumatic extrusion-based bioprinting with analytical assays to enable efficient drug screening in 3D melanoma models. To address this gap, this study developed a simple and highly reproducible approach to fabricate a 3D A375 melanoma cell culture model using the pneumatic extrusion-based bioprinting technology. To optimise this method, the bioprinting parameters for producing 3D cell cultures in a 96-well plate were adjusted to improve reproducibility while maintaining the desired droplet size and a cell viability of 92.13± 6.02%. The cross-linking method was optimised by evaluating cell viability and proliferation of the 3D bioprinted cells in three different concentrations of calcium chloride. The lower concentration of 50 mM resulted in higher cell viability and increased cell proliferation after 9 days of incubation. The A375 cells exhibited a steadier proliferation rate in the 3D bioprinted cell cultures, and tended to aggregate into spheroids, whereas the 2D cell cultures generally formed monolayered cell sheets. In addition, we evaluated the drug responses of four different anti-cancer drugs on the A375 cells in both the 2D and 3D cell cultures. The 3D cell cultures exhibited higher levels of drug resistance in all four tested anti-cancer drugs. This method presents a simple and cost-effective method of producing and analysing 3D cell culture models that do not add additional complexity to current assays and shows considerable potential for advancing 3D cell culture models' drug efficacy evaluations.
    Keywords:  3D cell culture models; droplet-based extrusion bioprinting; extrusion-based bioprinting; high-throughput bioprinting; high-throughput drug screening
    DOI:  https://doi.org/10.1088/1748-605X/ad651f
  12. J Med Chem. 2024 Jul 19.
    Rational In Silico Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket.
    Michael Desgagné, Antoine Désilets, Sára Ferková, Matthieu Lepage, Olivier Perreault, Alexandre Joushomme, Gabriel Lemieux, Walid Guerrab, Ulrike Froehlich, Christian Comeau, Philippe Sarret, Richard Leduc, Pierre-Luc Boudreault.
      TMPRSS6 is a potential therapeutic target for the treatment of iron overload due to its role in regulating levels of hepcidin. Although potent TMPRSS6 inhibitors have been previously developed, their lack of specificity requires optimization to avoid potential side effects before pursuing preclinical development with in vivo models. Here, using computer-aided drug design based on a TMPRSS6 homology model, we reveal that the S2 position of TMPRSS6 offers a potential avenue to achieve selectivity against other members of the TTSP family. Accordingly, we synthesized novel peptidomimetic molecules containing lipophilic amino acids at the P2 position to exploit this unexplored pocket. This enabled us to identify TMPRSS6-selective small molecules with low nanomolar affinity. Finally, pharmacokinetic parameters were determined, and a compound was found to be potent in cellulo toward its primary target while retaining TTSP-subtype selectivity and showing no signs of alteration in in vitro TEER experiments.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c00922
  13. EJNMMI Radiopharm Chem. 2024 Jul 15. 9(1): 52
    Preclinical evaluation of CXCR4 peptides for targeted radionuclide therapy in glioblastoma.
    Anthony Waked, Melissa Crabbé, Virginie Neirinckx, Sunay Rodriguez Pérez, Jasmien Wellens, Bernard Rogister, M Abderrafi Benotmane, Koen Vermeulen.
       BACKGROUND: Glioblastoma (GBM), is the most fatal form of brain cancer, with a high tendency for recurrence despite combined treatments including surgery, radiotherapy, and chemotherapy with temozolomide. The C-X-C chemokine receptor 4 (CXCR4) plays an important role in tumour radioresistance and recurrence, and is considered as an interesting GBM target. TRT holds untapped potential for GBM treatment, with CXCR4-TRT being a promising strategy for recurrent GBM treatment. Our study focuses on the preclinical assessment of different 177Lu-labelled CXCR4-targeting peptides, CTCE-9908, DV1-K-DV3, and POL3026 for GBM treatment and exploring some of the radiobiological mechanisms underlying these therapies.
    RESULTS: All three DOTA-conjugated peptides could be radiolabelled with 177Lu with > 95% radiochemical yield. Binding studies show high specific binding of [177Lu]Lu-DOTA-POL3026 to U87-CXCR4 + cells, with 42% of the added activity binding to the membrane at 1 nM, and 6.5% internalised into the cells. In the presence of the heterologous CXCR4 blocking agent, AMD11070, membrane binding was reduced by 95%, a result confirmed by quantitative in vitro autoradiography of orthotopic GBM xenograft sections. An activity-dependent decrease in cell viability was observed for [177Lu]Lu-DOTA-DV1-K-DV3 and [177Lu]Lu-DOTA-POL3026, along with a slight increase in the induction of apoptotic markers. Additionally, the expression of γH2AX increased in a time-and activity-dependent manner. Ex vivo biodistribution studies with [177Lu]Lu-DOTA-POL3026 show uptake in the tumour reaching a SUV of 1.9 at 24 h post-injection, with higher uptake in the kidneys, lungs, spleen, and liver. Dosimetry estimations show an absorbed dose of 0.93 Gy/MBq in the tumour. A blocking study with AMD11070 showed a 38% reduction in tumour uptake, with no significant reduction observed in µSPECT imaging. Although no brain uptake was observed in the ex vivo biodistribution study, autoradiography on U87-CXCR4 + tumour inoculated mouse brain slices shows non-specific binding in the brain, next to high specific binding to the tumour.
    CONCLUSIONS: In conclusion, we compared different 177Lu-radiolabelled CXCR4-targeting peptides for their binding potential in GBM, and demonstrated their varied cytotoxic action against GBM cells in vitro, with POL3026 being the most promising, causing considerable DNA damage. Though the peptide's systemic biodistribution remains to be improved, our data demonstrate the potential of [177Lu]Lu-DOTA-POL3026 for CXCR4-TRT in the context of GBM.
    DOI:  https://doi.org/10.1186/s41181-024-00282-y
  14. Curr Opin Chem Biol. 2024 Jul 17. pii: S1367-5931(24)00077-2. [Epub ahead of print]81 102501
    Recent advances in methods for quantifying the cell penetration of macromolecules.
    Nefeli Batistatou, Joshua A Kritzer.
      As the landscape of macromolecule therapeutics advances, drug developers are continuing to aim at intracellular targets. To activate, inhibit, or degrade these targets, the macromolecule must be delivered efficiently to intracellular compartments. Quite often, there is a discrepancy between binding affinity in biochemical assays and activity in cell-based assays. Identifying the bottleneck for cell-based activity requires robust assays that quantify total cellular uptake and/or cytosolic delivery. Recognizing this need, chemical biologists have designed a plethora of assays to make this measurement, each with distinct advantages and disadvantages. In this review, we describe the latest and most promising developments in the last 3 to 4 years.
    Keywords:  Cell penetration; Drug delivery; Oligonucleotide therapeutics; Peptide therapeutics
    DOI:  https://doi.org/10.1016/j.cbpa.2024.102501
  15. Protein J. 2024 Jul 16.
    Identification and Design of Novel Potential Antimicrobial Peptides Targeting Mycobacterial Protein Kinase PknB.
    Hemchandra Deka, Atul Pawar, Monishka Battula, Ayman A Ghfar, Mohamed E Assal, Rupesh V Chikhale.
      Antimicrobial peptides have gradually gained advantages over small molecule inhibitors for their multifunctional effects, synthesising accessibility and target specificity. The current study aims to determine an antimicrobial peptide to inhibit PknB, a serine/threonine protein kinase (STPK), by binding efficiently at the helically oriented hinge region. A library of 5626 antimicrobial peptides from publicly available repositories has been prepared and categorised based on the length. Molecular docking using ADCP helped to find the multiple conformations of the subjected peptides. For each peptide served as input the tool outputs 100 poses of the subjected peptide. To maintain an efficient binding for relatively a longer duration, only those peptides were chosen which were seen to bind constantly to the active site of the receptor protein over all the poses observed. Each peptide had different number of constituent amino acid residues; the peptides were classified based on the length into five groups. In each group the peptide length incremented upto four residues from the initial length form. Five peptides were selected for Molecular Dynamic simulation in Gromacs based on higher binding affinity. Post-dynamic analysis and the frame comparison inferred that neither the shorter nor the longer peptide but an intermediate length of 15 mer peptide bound well to the receptor. Residual substitution to the selected peptides was performed to enhance the targeted interaction. The new complexes considered were further analysed using the Elastic Network Model (ENM) for the functional site's intrinsic dynamic movement to estimate the new peptide's role. The study sheds light on prospects that besides the length of peptides, the combination of constituent residues equally plays a pivotal role in peptide-based inhibitor generation. The study envisages the challenges of fine-tuned peptide recovery and the scope of Machine Learning (ML) and Deep Learning (DL) algorithm development. As the study was primarily meant for generation of therapeutics for Tuberculosis (TB), the peptide proposed by this study demands meticulous invitro analysis prior to clinical applications.
    Keywords:  ADCP; Elastic Network Model (ENM); Gromacs; Serine/threonine Protein Kinase (STPK)
    DOI:  https://doi.org/10.1007/s10930-024-10218-9
  16. Cell Death Dis. 2024 Jul 18. 15(7): 513
    Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.
    Charles L Bidgood, Lisa K Philp, Anja Rockstroh, Melanie Lehman, Colleen C Nelson, Martin C Sadowski, Jennifer H Gunter.
      Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.
    DOI:  https://doi.org/10.1038/s41419-024-06893-2
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