Peptide-Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics.

Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide-drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody-drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide-drug conjugate design and optimization, such as peptide/small-molecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide-drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms.

Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action. One such peptide is apidaecin (Api), which inhibits translation termination through stabilization of the quaternary complex of the ribosome-apidaecin-tRNA-release factor. Synthetic derivatives of apidaecin have been developed, but structure-guided modifications have yet to be considered. In this work, we have focused on modifying key residues in the Api sequence that are responsible for the interactions that stabilize the quaternary complex. We present one of the first examples of a highly modified Api peptide that maintains its antimicrobial activity and interaction with the translation complex. These findings establish a starting point for further structure-guided optimization of Api peptides.

Hollow Gold Nanosphere Templated Synthesis of PEGylated Hollow Gold Nanostars and Use for SERS Detection of Amyloid Beta in Solution.

Hollow gold nanospheres (HGNs) have been used as the template for seed-mediated growth of multibranched hollow gold nanostars (HNS). The HGNs were synthesized via anerobic reduction of cobalt chloride to cobalt nanoparticles and then formation of a gold shell via galvanic replacement followed by the oxidation of the cobalt core. We obtained control of the inner core size of the HGNs by increasing the size of the sacrificial cobalt core and by varying the ratio of B(OH)3/BH4 using boric acid rather than 48 h aged borohydride. We synthesized the HNS by reducing Au3+ ions in the presence of Ag+ ions using ascorbic acid, creating a spiky morphology that varied with the Au3+/Ag+ ratio. A broadly tunable localized surface plasmon resonance was achieved through control of both the inner core and the spike length. Amyloid beta (Aß) was conjugated to the HNS by using a heterobifunctional PEG linker and identified by the vibrational modes associated with the conjugated ring phenylalanine side chain. A bicinchoninic acid assay was used to determine the concentration of Aß conjugated to HNS as 20 nM, which is below the level of Aß that negatively affects long-term potentiation. Both the core size and spike length were shown to affect the optical properties of the resulting nanostructures. This HGN templated method introduced a new parameter for enhancing the plasmonic properties of gold nanostars, namely, the addition of a hollow core. Hollow gold nanostars are highly desirable for a wide range of applications, including high sensitivity disease detection and monitoring.

First Synthesis of Mn-Doped Cesium Lead Bromide Perovskite Magic Sized Clusters at Room Temperature.

Mn-doped CsPbBr3 perovskite magic sized clusters (PMSCs) are synthesized for the first time using benzoic acid and benzylamine as passivating ligands and MnCl2·4H2O and MnBr2 as the Mn2+ dopant sources at room temperature. The same approach is used to prepare Mn-doped CsPbBr3 perovskite quantum dots (PQDs). The concentration of MnX2 (X = Cl or Br) affects the excitonic absorption of the PMSCs and PQDs. A higher concentration of MnX2 favors PMSCs over PQDs as well as higher photoluminescence (PL) quantum yields (QYs) and PL stability. The large ratio between the characteristic Mn emission (∼590 nm) and the host band-edge emission shows efficient energy transfer from the host exciton to the Mn2+ dopant. PL excitation, electron paramagnetic resonance, and time-resolved PL results all support Mn2+ doping in CsPbBr3, which likely replaces Pb2+ ions. This study establishes a new method for synthesizing Mn-doped PMSCs with good PL stability, high PLQY and highly effective passivation.

Size and temperature dependence of photoluminescence of hybrid perovskite nanocrystals.

In this work, we studied the effects of particles' size and temperature on the photoluminescence (PL) of CH3NH3PbBr3 perovskite nanocrystals (PNCs), with the PNC size controlled by varying the surface passivating ligands. The structural and optical properties of the PNCs were investigated using UV-Vis and PL spectroscopy, revealing strong quantum confinement effects. Temperature dependent PL measurements showed the spectral blue shift of the PL peak for the small PNCs (3.1 ± 0.2 nm) with decreasing temperature from 300 K to 20 K, which is opposite to the red shift with decreasing temperature observed for large- (9.2 ± 0.5 nm) and middle-sized (5.1 ± 0.3 nm) PNCs. The PL lifetime also increased with increasing temperature for the larger PNCs, while it remained about the same for the small and middle-sized PNCs. This increase in lifetime with temperature is attributed to exciton dissociation to free carriers at higher temperatures and to the formation of polar domains in the PNCs. However, the small and middle-sized PNCs did not show such a trend, which may be due to efficient defect passivation as higher concentration of 3-aminopropyl trimethoxysilane (APTMS) was used and to the role of particle size in surface state delocalization. Cryo-X-ray diffraction showed no new peak formation or peak splitting as temperature was varied, which suggests efficient crystal phase stabilization in PNCs of all three sizes controlled by the concentration of APTMS. These results emphasize the importance of size and surface properties of PNCs in their optical properties such as PL quantum yield, PL lifetime, and crystal phase stability.

Tuning from Quantum Dots to Magic Sized Clusters of CsPbBr3 Using Novel Planar Ligands Based on the Trivalent Nitrate Coordination Complex.

We report the first demonstration of using trivalent metal hydrated nitrate coordination complexes (TMHNCCs) as novel passivation ligands to control the synthesis of magic sized clusters (MSCs) and quantum dots (QDs) of CsPbBr3 perovskite at room temperature. We can easily tune from QDs to MSCs or produce a mixture of the two by changing the amount of TMHNCC ligands used, with more ligands favoring MSCs. The original TMHNCC introduced, aluminum nitrate nonahydrate [ANN, Al(NO3)3·9H2O], led to the production of aluminum dihydroxide nitrate tetrahydrate {ADNT, [Al(OH)2(NO3)]·4H2O}, with the assistance of oleic acid (OA) and oleylamine (OAm). Through several control experiments, we determined that ADNT is the primary ligand for effectively passivating the MSCs and QDs, with OAm being essential for deprotonating ANN and OA for adjusting the pH of the reaction system. We suggest that ADNT is planar on the surface of the MSCs or QDs with its NO3- and OH- groups binding to the Cs+ and Pb2+ defect sites and Al3+ binding to the Br- defect sites of the MSCs or QDs.

Synergistic Surface Passivation of CH3 NH3 PbBr3 Perovskite Quantum Dots with Phosphonic Acid and (3-Aminopropyl)triethoxysilane.

CH3 NH3 PbBr3 perovskite quantum dots (PQDs) are synthesized by using four different linear alkyl phosphonic acids (PAs) in conjunction with (3-aminopropyl)triethoxysilane (APTES) as capping ligands. The resultant PQDs are characterized by means of XRD, TEM, Raman spectroscopy, FTIR spectroscopy, UV/Vis, photoluminescence (PL), time-resolved PL, and X-ray photoelectron spectroscopy (XPS). PA chain length is shown to control the PQD size (ca. 2.9-4.2 nm) and excitonic absorption band positions (λ=488-525 nm), with shorter chain lengths corresponding to smaller sizes and bluer absorptions. All samples show a high PL quantum yield (ca. 46-83 %) and high PL stability; this is indicative of a low density of band gap trap states and effective surface passivation. Stability is higher for smaller PQDs; this is attributed to better passivation due to better solubility and less steric hindrance of the shorter PA ligands. Based on the FTIR, Raman, and XPS results, it is proposed that Pb2+ and CH3 NH3 + surface defects are passivated by R-PO3 2- or R-PO2 (OH)- , whereas Br- surface defects are passivated by R-NH3 + moieties. This study establishes the combination of PA and APTES ligands as a highly effective dual passivation system for the synergistic passivation of multiple surface defects of PQDs through primarily ionic bonding.

Enhanced Photocatalytic Activity of Directly Assembled Fe2O3/Gd2O3@TiO2-Based Nanosheets.

TiO2-based nanosheets (TNSs) modified with surface-enriched Fe2O3 and Gd2O3 nanoparticles (NPs) have been synthesized via a direct interfacial assembly strategy. The TNSs with a unique two-dimensional structure are favorable for supporting Fe2O3 and Gd2O3 NPs for photocatalytic applications. The prepared samples were characterized using scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), Raman spectroscopy (Raman), BET, X-ray photoelectron spectroscopy (XPS), UV-Vis diffuse reflectance spectra (DRS), photoluminescence (PL) spectroscopy and the surface photocurrent (SPC) technique. The photocatalysts exhibited large specific surface area (160-260 m²/g). The co-modification with Fe2O3 and Gd2O3 NPs influenced the crystallinity and surface area of the TNSs, and improved visible-light absorption. Surface photocurrent and PL studies revealed that the photogenerated charge carrier separation efficiency could be improved by an appropriate amount of NPs. The optimized nanostructure exhibited photocatalytic efficiency for rhodamine B (RhB) degradation and H2 production is 5.66-fold and 2.99-fold respectively than those of TNSs under visible-light irradiation. The enhancement is attributed to the combined effect of Gd2O3 and Fe2O3 NPs in the Fe2O3/Gd2O3@TNSs composites. The simultaneous use of two different types of NPs led to a fast separation and slow recombination of photoinduced electron-hole pairs. A mechanism is proposed to explain the enhanced visible-light photocatalytic activity.

Detection of Saturated Fatty Acids Associated with a Self-Healing Synthetic Biological Membrane Using Fiber-Enhanced Surface Enhanced Raman Scattering.

The Synthetic Biological Membrane (SBM) project at NASA Ames developed a portable, self-repairing wastewater purification system. The self-repair process relies upon secreted fatty acids from a genetically engineered organism. However, solubilized fatty acids are difficult to detect using conventional methods. Surface-enhanced Raman scattering (SERS) was used to successfully detect solubilized fatty acids with the following limits of detection: 10-9, 10-8, 10-9, and 10-6 M for decanoic acid, myristic acid, palmitic acid, and stearic acid, respectively. Additionally, hollow core photonic crystal fiber (HCPCF) was applied as the sampling device together with SERS to develop in situ surveillance of the production of fatty acids. Using SERS + HCPCF yielded an 18-fold enhancement in SERS signal for the CH2 twist peak at 1295 cm-1 as compared to SERS alone. The results will help the SBM project to integrate a self-healing wastewater purification membrane into future water recycling systems.

Detection of Saturated Fatty Acids Associated with a Self-Healing Synthetic Biological Membrane Using Fiber-Enhanced Surface Enhanced Raman Scattering.

The Synthetic Biological Membrane (SBM) project at NASA Ames developed a portable, self-repairing wastewater purification system. The self-repair process relies upon secreted fatty acids from a genetically engineered organism. However, solubilized fatty acids are difficult to detect using conventional methods. Surface-enhanced Raman scattering (SERS) was used to successfully detect solubilized fatty acids with the following limits of detection: 10-9 M, 10-8 M, 10-9 M, and 10-6 M for decanoic acid, myristic acid, palmitic acid, and stearic acid, respectively. Additionally, hollow core photonic crystal fiber (HCPCF) was applied as the sampling device together with SERS to develop in situ surveillance of the production of fatty acids. Using SERS + HCPCF yielded an 18 fold enhancement in SERS signal for the CH2 twist peak at 1295 cm-1 as compared to SERS alone. The results will help the SBM project to integrate a self-healing wastewater purification membrane into future water recycling systems.