Porphyrin Peptide Research Articles

A zinc–porphyrin–peptide conjugate via “click-chemistry”: synthesis and amyloid-β interaction

A Zn–porphyrin–peptide conjugate was obtained by click-reaction between an alkyne-porphyrin and the azido-peptide of KLVFF. The peptide showed an induced dichroic signal in the presence of Aβ42 and no toxicity on neuronal cells.

Hydrogen evolution catalysis by a cobalt porphyrin peptide: A proposed role for porphyrin propionic acid groups

Cobalt microperoxidase-11 (CoMP11-Ac) is a cobalt porphyrin-peptide catalyst for hydrogen (H2) evolution from water. Herein, we assess electrocatalytic activity of CoMP11-Ac from pH 1.0–10.0. This catalyst remains intact and active under highly acidic conditions (pH 1.0) that are desirable for maximizing H2 evolution activity. Analysis of electrochemical data indicate that H2 evolution takes place by two pH-dependent mechanisms. At pH < 4.3, a proton transfer mechanism involving the propionic acid groups of the porphyrin is proposed, decreasing the catalytic overpotential by 280 mV.

Versatile Synthesis of Multivalent Porphyrin-Peptide Conjugates by Direct Porphyrin Construction on Resin.

Multifunctional porphyrin–peptide conjugates with different propensities for self‐assembly into various supramolecular nanoarchitectures play important roles in advanced materials and biomedical research. However, preparing prefunctionalized core porphyrins by traditional low‐yielding statistical synthesis and purifying them after peptide ligation through many rounds of HPLC purification is tedious and unsustainable. Herein, we report a novel integrated solid‐phase synthetic protocol for the construction of porphyrin moieties from simple aldehydes and dipyrromethanes on resin‐bound peptides directly to form mono‐, cis/trans‐di‐, and trivalent porphyrin–peptide conjugates in a highly efficient and controllable manner; moreover, only single final‐stage HPLC purification of the products is needed. This efficient strategy enables the rapid, greener, and substrate‐controlled diversity‐oriented synthesis of multivalent porphyrin–(long) peptide conjugate libraries for multifarious biological and materials applications.

Versatile Synthesis of Multivalent Porphyrin–Peptide Conjugates by Direct Porphyrin Construction on Resin

AbstractMultifunctional porphyrin–peptide conjugates with different propensities for self‐assembly into various supramolecular nanoarchitectures play important roles in advanced materials and biomedical research. However, preparing prefunctionalized core porphyrins by traditional low‐yielding statistical synthesis and purifying them after peptide ligation through many rounds of HPLC purification is tedious and unsustainable. Herein, we report a novel integrated solid‐phase synthetic protocol for the construction of porphyrin moieties from simple aldehydes and dipyrromethanes on resin‐bound peptides directly to form mono‐, cis/trans‐di‐, and trivalent porphyrin–peptide conjugates in a highly efficient and controllable manner; moreover, only single final‐stage HPLC purification of the products is needed. This efficient strategy enables the rapid, greener, and substrate‐controlled diversity‐oriented synthesis of multivalent porphyrin–(long) peptide conjugate libraries for multifarious biological and materials applications.

Targeting Zika Virus with New Brain- and Placenta-Crossing Peptide-Porphyrin Conjugates.

Viral disease outbreaks affect hundreds of millions of people worldwide and remain a serious threat to global health. The current SARS-CoV-2 pandemic and other recent geographically- confined viral outbreaks (severe acute respiratory syndrome (SARS), Ebola, dengue, zika and ever-recurring seasonal influenza), also with devastating tolls at sanitary and socio-economic levels, are sobering reminders in this respect. Among the respective pathogenic agents, Zika virus (ZIKV), transmitted by Aedes mosquito vectors and causing the eponymous fever, is particularly insidious in that infection during pregnancy results in complications such as foetal loss, preterm birth or irreversible brain abnormalities, including microcephaly. So far, there is no effective remedy for ZIKV infection, mainly due to the limited ability of antiviral drugs to cross blood–placental and/or blood–brain barriers (BPB and BBB, respectively). Despite its restricted permeability, the BBB is penetrable by a variety of molecules, mainly peptide-based, and named BBB peptide shuttles (BBBpS), able to ferry various payloads (e.g., drugs, antibodies, etc.) into the brain. Recently, we have described peptide–porphyrin conjugates (PPCs) as successful BBBpS-associated drug leads for HIV, an enveloped virus in which group ZIKV also belongs. Herein, we report on several brain-directed, low-toxicity PPCs capable of targeting ZIKV. One of the conjugates, PP-P1, crossing both BPB and BBB, has shown to be effective against ZIKV (IC50 1.08 µM) and has high serum stability (t1/2 ca. 22 h) without altering cell viability at all tested concentrations. Peptide–porphyrin conjugation stands out as a promising strategy to fill the ZIKV treatment gap.

Bioinspired porphyrin-peptide supramolecular assemblies and their applications.

Inspired by the hierarchical chiral assembly of porphyrin-proteins in photosynthetic systems, the hierarchical self-assembly of porphyrin-amino acids/peptides provides a novel strategy for constructing functional materials. How to artificially simulate the assembly of porphyrins, proteins, and other cofactors in the photosynthesis system to obtain persistent strong light capture, charge separation and catalytic reactions has become an important concern in the construction of biomimetic photosynthesis systems. This paper summarizes the different assembly strategies adopted in recent years, the effects of driving forces on self-assembly, and the application of porphyrin-peptides in catalysis and biomedicine, and briefly discusses the challenges and prospects for future research.

Penetrating the Blood-Brain Barrier with New Peptide-Porphyrin Conjugates Having anti-HIV Activity.

Passing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide–drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide–porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.

Photoelectric conversion based on peptide–porphyrin conjugates assembled hydrogel

Peptide–porphyrin conjugates facilitated porphyrin to participate in the assembly of hydrogel, improving the utilization of porphyrin and photoelectric conversion efficiency.

Self-assembled supramolecular nanostructure photosensitizers for photocatalytic hydrogen evolution

Supramolecular self-assembly as a breakthrough methodology in the nanoscience and nanotechnology fields has attracted increasing attention. Highly ordered self-assembled supramolecular nanostructures aim to emulate natural light-harvesting and energy transfer and electron transfer processes, which have been an active and rapidly developing field for visible-light-driven photocatalytic applications. This Research Update aims to present the recent progress of the self-assembly of π-conjugated molecules, including perylene diimides (PDIs), porphyrin, and co-assembly of peptide–porphyrin as well as the shape-defined functional hierarchical structures. First, the basic principles of π-conjugated molecular structure design are described. The two nitrogen positions and the bay positions of PDIs can effectively regulate their electronic properties and geometric skeleton, and the functional groups and the good solvents of porphyrin effectively determine the choice of self-assembly methods. Then, the key morphology dependent optoelectronic properties and charge-transport and energy-transport functionalities are also discussed. These self-assembled supramolecular nanostructures’ inherent optoelectronic properties correlated with applications in photocatalytic water splitting into hydrogen evolution are overviewed. By now, the self-assembled In(III) meso-tetraphenylporphine (InTPP) porphyrin nanostructures exhibited the highest photocatalytic hydrogen generation activity among the reported supramolecular nanostructures owing to the central metal of porphyrin and small size of the InTPP nanostructure. Finally, perspectives on the crucial issues and potential future research directions are addressed. This Research Update will provide a new reference for building high performance, stable, and durable photosensitizers based on the supramolecular assembly.

Buffer Pk a Impacts the Mechanism of Hydrogen Evolution Catalyzed By a Cobalt Porphyrin-Peptide

The effect of buffer pK a on the mechanism of electrochemical hydrogen evolution catalyzed by a cobalt porphyrin peptide (CoMP11-Ac) at constant pH is presented. The addition of buffer to CoMP11-Ac in water and KCl leads to an enhancement of the catalytic current of up to 200-fold relative to its value in the absence of a buffer. Two distinct catalytic regimes are identified as a function of the buffer pK a. In the presence of buffers with pK a ≤ 7.4, a fast catalysis regime limited by diffusion of buffer is reached. The catalytic half-wave potential (E h ) shifts anodically (from −1.42 to −1.26 V vs Ag/AgCl/KCl(1M)) as the buffer pK a decreases from 7.4 to 5.6, proposed to result from fast Co(III)-H formation following the catalysis-initiating Co(II/I) reduction. With higher-pK a buffers (pK a > 7.7), an E h = −1.42 V, proposed to reflect the Co(II/I) couple, is maintained independent of the buffer pK a, consistent with rate-limiting Co(III)-H formation under these conditions. We conclude that the buffer species pK a impacts catalytic current and potential and the rate-determining step of the reaction.

Acid-Activatable Transmorphic Peptide-Based Nanomaterials for Photodynamic Therapy.

Inspired by the dynamic morphology control of molecular assemblies in biological systems, we have developed pH‐responsive transformable peptide‐based nanoparticles for photodynamic therapy (PDT) with prolonged tumor retention times. The self‐assembled peptide–porphyrin nanoparticles transformed into nanofibers when exposed to the acidic tumor microenvironment, which was mainly driven by enhanced intermolecular hydrogen bond formation between the protonated molecules. The nanoparticle transformation into fibrils improved their singlet oxygen generation ability and enabled high accumulation and long‐term retention at tumor sites. Strong fluorescent signals of these nanomaterials were detected in tumor tissue up to 7 days after administration. Moreover, the peptide assemblies exhibited excellent anti‐tumor efficacy via PDT in vivo. This in situ fibrillar transformation strategy could be utilized to design effective stimuli‐responsive biomaterials for long‐term imaging and therapy.

Buffer pKa Impacts the Mechanism of Hydrogen Evolution Catalyzed by a Cobalt Porphyrin-Peptide.

The effect of buffer pKa on the mechanism of electrochemical hydrogen evolution catalyzed by a cobalt porphyrin peptide (CoMP11-Ac) at constant pH is presented. The addition of buffer to CoMP11-Ac in water and KCl leads to an enhancement of the catalytic current of up to 200-fold relative to its value in the absence of a buffer. Two distinct catalytic regimes are identified as a function of the buffer pKa. In the presence of buffers with pKa ≤ 7.4, a fast catalysis regime limited by diffusion of buffer is reached. The catalytic half-wave potential (Eh) shifts anodically (from -1.42 to -1.26 V vs Ag/AgCl/KCl(1M)) as the buffer pKa decreases from 7.4 to 5.6, proposed to result from fast Co(III)-H formation following the catalysis-initiating Co(II/I) reduction. With higher-pKa buffers (pKa > 7.7), an Eh = -1.42 V, proposed to reflect the Co(II/I) couple, is maintained independent of the buffer pKa, consistent with rate-limiting Co(III)-H formation under these conditions. We conclude that the buffer species pKa impacts catalytic current and potential and the rate-determining step of the reaction.

Buffer Pka Impacts the Mechanism of Hydrogen Evolution in Water Catalyzed By a Cobalt Porphyrin-Peptide

A detailed study of the impact of buffer pKa (pKa 5.6 to 10.5) on electrochemical hydrogen evolution at constant pH catalyzed by CoMP11-Ac, a cobalt porphyrin peptide, is presented. The addition of buffer leads to a significant enhancement of the catalytic current of up to 20-fold relative to its value in absence of buffer. Two distinct catalytic regimes are identified based on the buffer pKa . In the presence of buffers with pKa ≤ 7.4 a fast catalysis regime limited by diffussion of buffer is reached. The catalytic half-wave potential (Eh ) shifts anodically (from -1.42 to -1.26 V vs Ag/AgCl/KCl(1M)) as the buffer pKa decreases from 7.4 to 5.6, proposed to result from fast Co(III)-H formation following the catalysis-initiating Co(II/I) reduction. With higher-pKa buffers (pKa > 7.7), an Eh = -1.42 V reflecting the potential of the Co(II/I) couple is maintained independent of the buffer pKa , consistent with a rate-limiting Co(III)-H formation under these conditions. We conclude that the buffer species pK a, even at constant pH, can have a large effect on both catalytic current and potential, as well as the rate-determining step of the reaction. Thus, buffer is a factor to consider in optimizing reaction conditions for hydrogen-evolving catalysis and for other proton-requiring reactions in water. Finally, buffer acids are shown to be a probe for studying hydrogen evolution mechanism in water.

Tuning the morphology of mesoscopic structures of porphyrin macrocycles functionalized by an antimicrobial peptide

The aggregation properties of two peptide–porphyrin conjugates were investigated by optical spectroscopy and microscopy imaging with nanometer resolution. Specifically, a tetraphenylporphyrin platform was functionalized by (L)-magainin, a 23-residue long antimicrobial peptide, and by a (L)-magainin analogue differing from the parent peptide by a single residue substitution, [Formula: see text] an Ala vs. Phe replacement in the position 5 of the peptide chain. Spectroscopic and microscopy results show that this single-site substitution has a small effect on the secondary structure attained by the two peptide analogues, but deeply affects the morphology of the mesoscopic structures deposited on hydrophilic mica from methanol/water solutions. In particular, only the Ala-substituted peptide-porphyrin conjugate was shown to be able to form micrometric fibrils, coating homogeneously a hydrophilic mica surface. These results pave the way for potential applications of porphyrin-peptide compounds in localized photodynamic therapy and for designing solid-state stereoselective sensors.

Morphological Control of Chromophore Spin State in Zinc Porphyrin-Peptide Assemblies.

Self-assembled peptide micelles and fibers demonstrate unique control over the photophysical properties of the bound, light-activated chromophore, zinc protoporphyrin IX, (PPIX)Zn. Micelles encapsulate either a mixture of uncoordinated and coordinated (PPIX)Zn or all coordinated depending on the ratio of peptide/porphyrin. As the ratio increases toward a 1:1 micelle/porphyrin ratio, providing the chromophore with a discrete coordination environment reminiscent of unstructured proteins, the micelles favor triplet formation. Fibers, however, promote a linear array of porphyrin molecules that dictates exciton hopping and excimer formation at ratios as high as 60:1, peptide/porphyrin. However, even in fibers, the formation of the triplet species increases with increasing peptide/porphyrin ratio due to increased spatial separation between neighboring chromophores facilitating intersystem crossing. Full characterization of the micelles structures and comparison to the fibers lead to the comparison with natural systems and the ability to control the excited populations that have utility in photocatalytic processes. In addition, the incorporation of a second chromophore, heme, yields an electron transfer pathway in both micelles and fibers that highlights the utility of the peptide assemblies when engineering multichromophore arrays as inspired by natural, photosynthetic proteins.

Chirality and spatially pre-organized multi-porphyrinoids

We report herein that chiral and enantiopure compounds such nucleosides and peptides can pre-organize multi-porphyrinic systems and influence their properties. The first example given concerns star-shaped mutli-porphyrins with chiral and enantiopure nucleosidic linkers. If the configuration is indeed a star-shaped nanomolecule, it appears that the induced conformation is nothing as expected. The four peripheral Zn(II) porphyrins collapse over the free-base central one, inducing totally different photo-physical properties. Despite a minor expected light energy harvesting behavior, the principal capability of this system is to quench the collected light energy and convert it from radiative to non-radiative de-activation. The second example concerns polypeptides with pendant porphyrins. The peptidic backbone confers to the systems, after a certain degree of oligomerization, a 3[Formula: see text] right handed helical conformation which induces cavities within the multi-porphyrinc architecture, ready to welcome guests and render, for example, the complexation of C[Formula: see text] much easier. We thus have constructed novel organic photovoltaic systems using supramolecular complexes of porphyrin–peptide oligomers with fullerene clusters. The composite cluster OTE/SnO[Formula: see text] electrode prepared with (P(ZnP)[Formula: see text] C[Formula: see text], exhibits an impressive incident photon-to-photocurrent efficiency (IPCE) with values reaching as high as 56%. The power conversion efficiency of the (P(H[Formula: see text]P)[Formula: see text] C[Formula: see text] modified electrode reaches 1.6%, which is 40 times higher than the value (0.043%) of the porphyrin monomer (P(H[Formula: see text]P)[Formula: see text] [Formula: see text] C[Formula: see text] modified electrode. Thus, the organization approach between porphyrins and fullerenes with polypeptide structures is promising, and may make it possible to further improve the light energy conversion properties by using a larger number of porphyrins in a polypeptide unit.

Porphyrin–peptide conjugates in biomedical applications

AbstractThe conjugation of peptides to porphyrins and related tetrapyrrole based macrocycles have extended their applications in biological systems, where the photophysical properties of these molecules and their ability to coordinate metals can be exploited for detecting and opposing to the onset of important diseases. This review presents a survey of the published literature over last years on biomedical applications of these hybrid compounds, mostly in the field of photodynamic therapy (PDT), but also in sensing key metabolites and peculiar structures of biomolecules in living systems. Peptides based strategies to improve the efficacy of the photosensitizer (PS) in PDT will be discussed, as well as solutions to overcome some limitations recently emerged in the use of peptides as delivery vehicles. An overview on possible application of porphyrin–peptide conjugates in detection of biomarkers of physiological and pathological states will be also presented.

Biological Photothermal Nanodots Based on Self-Assembly of Peptide–Porphyrin Conjugates for Antitumor Therapy

Photothermal agents can harvest light energy and convert it into heat, offering a targeted and remote-controlled way to destroy carcinomatous cells and tissues. Inspired by the biological organization of polypeptides and porphyrins in living systems, here we have developed a supramolecular strategy to fabricate photothermal nanodots through peptide-modulated self-assembly of photoactive porphyrins. The self-assembling nature of porphyrins induces the formation of J-aggregates as substructures of the nanodots, and thus enables the fabrication of nanodots with totally inhibited fluorescence emission and singlet oxygen production, leading to a high light-to-heat conversion efficiency of the nanodots. The peptide moieties not only provide aqueous stability for the nanodots through hydrophilic interactions, but also provide a spatial barrier between porphyrin groups to inhibit the further growth of nanodots through the strong π-stacking interactions. Thermographic imaging reveals that the conversion of light to heat based on the nanodots is efficient in vitro and in vivo, enabling the nanodots to be applied for photothermal acoustic imaging and antitumor therapy. Antitumor therapy results show that these nanodots are highly biocompatible photothermal agents for tumor ablation, demonstrating the feasibility of using bioinspired nanostructures of self-assembling biomaterials for biomedical photoactive applications.

Mimicking Primitive Photobacteria: Sustainable Hydrogen Evolution Based on Peptide–Porphyrin Co‐Assemblies with a Self‐Mineralized Reaction Center

AbstractMolecular evolution, with self‐organization of simple molecules towards complex functional systems, provides a new strategy for biomimetic architectonics and perspectives for understanding the complex processes of life. However, there remain many challenges to fabrication of systems comprising different types of units, which interact with one another to perform desired functions. Challenges arise from a lack of stability, dynamic properties, and functionalities that reconcile with a given environment. A co‐assembling fiber system composed of simple peptide and porphyrin is presented. This material is considered a prebiotic assembly of molecules that can be rather stable and flexibly self‐functionalized with the assistance of visible light in a “prebiotic soup”; acidic (pH 2), hot (70 °C), and mineral‐containing (Na+, Ti4+, Pt2+, and so forth) water. The co‐assembled peptide–porphyrin fiber, with self‐mineralized reaction centers, may serve as a primitive photobacteria‐like cellular model to achieve light harvesting, energy transfer, and ultimately sustainable hydrogen evolution.

Linker dependent chirality of solvent induced self-assembled structures of porphyrin-α-helical peptide conjugates.

The solvent-promoted aggregation of porphyrins covalently linked to medium length peptides occurs with the formation of chiral supramolecular structures if the peptide chain can adopt an α-helical secondary structure. The circular dichroism spectra of different porphyrin-peptide conjugates show that the chiral arrangement of the porphyrins in the aggregates does not depend on the screw-sense of the peptide helix. Experimental evidence and molecular dynamic simulations suggest that the linker between the porphyrin and the peptide helix is responsible for the overall chirality of supramolecular structures. In particular when the linker is a chiral α-amino acid it is possible to tune the morphology of the chiral aggregates by inverting the configuration of the chiral center.