ACS Bio & Med Chem Au最新文献

{"title":"Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist","authors":"Suneet Mehrotra,&nbsp;Sebastian Lam,&nbsp;Elizabeth Glenn,&nbsp;David Hymel,&nbsp;Christina A. Sanford,&nbsp;Qingyuan Liu,&nbsp;John Herich,&nbsp;Birgitte S. Wulff and Thomas H. Meek*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00016","DOIUrl":"10.1021/acsbiomedchemau.2c00016","url":null,"abstract":"<p >Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testing native molecules (NMU or its truncated version NMU-8) in a tissue-specific manner, in effect, taking advantage of the distinct receptor expression profiles. These strategies have proved quite useful despite the inherent limitations of overlapping receptor roles and potential compensatory influences of germline gene deletion. With these considerations in mind, the availability of potent, selective NMU compounds with appropriate pharmacokinetic profiles would advance the capabilities of investigators undertaking such efforts. Here, we evaluate a recently reported NMUR2-selective peptide (compound <b>17</b>) for its in vitro potency (mouse and human), binding affinity, murine pharmacokinetic properties, and in vivo effects. Despite being designed as an NMUR2 agonist, our results show compound <b>17</b> unexpectedly binds but does not have functional activity on NMUR1, thereby acting as an R1 antagonist while simultaneously being a potent NMUR2 agonist. Furthermore, evaluation of compound <b>17</b> across all known and orphan G-protein-coupled receptors demonstrates multiple receptor partners beyond NMUR2/R1 binding. These properties need to be appreciated for accurate interpretation of results generated using this molecule and may limit the broader ability of this particular entity in disentangling the physiological role of NMU receptor biology.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"370–375"},"PeriodicalIF":0.0,"publicationDate":"2022-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d8/e8/bg2c00016.PMC10125376.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9349791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collision-Induced Affinity Selection Mass Spectrometry for Identification of Ligands","authors":"Tin Mak,&nbsp;Jamie Rossjohn,&nbsp;Dene R. Littler,&nbsp;Miaomiao Liu* and Ronald J. Quinn*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00021","DOIUrl":"10.1021/acsbiomedchemau.2c00021","url":null,"abstract":"<p >Hyphenated mass spectrometry has been used to identify ligands binding to proteins. It involves mixing protein and compounds, separation of protein–ligand complexes from unbound compounds, dissociation of the protein–ligand complex, separation to remove protein, and injection of the supernatant into a mass spectrometer to observe the ligand. Here we report collision-induced affinity selection mass spectrometry (CIAS-MS), which allows separation and dissociation inside the instrument. The quadrupole was used to select the ligand–protein complex and allow unbound molecules to be exhausted to vacuum. Collision-induced dissociation (CID) dissociated the protein–ligand complex, and the ion guide and resonance frequency were used to selectively detect the ligand. A known SARS-CoV-2 Nsp9 ligand, oridonin, was successfully detected when it was mixed with Nsp9. We provide proof-of-concept data that the CIAS-MS method can be used to identify binding ligands for any purified protein.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 5","pages":"450–455"},"PeriodicalIF":0.0,"publicationDate":"2022-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/0e/bg2c00021.PMC10125361.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9356677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Class C Radical SAM Methyltransferases Involved in Anaerobic Heme Degradation”","authors":"Liju G. Mathew,&nbsp;Marley Brimberry and William N. Lanzilotta*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00025","DOIUrl":"10.1021/acsbiomedchemau.2c00025","url":null,"abstract":"[This corrects the article DOI: 10.1021/acsbiomedchemau.1c00047.].","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 6","pages":"655"},"PeriodicalIF":0.0,"publicationDate":"2022-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c8/2d/bg2c00025.PMC10114615.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9367174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Engineering of Miniproteins","authors":"Katarzyna Ożga,&nbsp; and ,&nbsp;Łukasz Berlicki*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00008","DOIUrl":"10.1021/acsbiomedchemau.2c00008","url":null,"abstract":"<p >The potential of miniproteins in the biological and chemical sciences is constantly increasing. Significant progress in the design methodologies has been achieved over the last 30 years. Early approaches based on propensities of individual amino acid residues to form individual secondary structures were subsequently improved by structural analyses using NMR spectroscopy and crystallography. Consequently, computational algorithms were developed, which are now highly successful in designing structures with accuracy often close to atomic range. Further perspectives include construction of miniproteins incorporating non-native secondary structures derived from sequences with units other than α-amino acids. Noteworthy, miniproteins with extended structures, which are now feasibly accessible, are excellent scaffolds for construction of functional molecules.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"316–327"},"PeriodicalIF":0.0,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10125317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9349790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient Strategy to Design Protease Inhibitors: Application to Enterovirus 71 2A Protease","authors":"Ting Chen,&nbsp;Cédric Grauffel,&nbsp;Wei-Zen Yang,&nbsp;Yi-Ping Chen,&nbsp;Hanna S. Yuan* and Carmay Lim*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00001","DOIUrl":"10.1021/acsbiomedchemau.2c00001","url":null,"abstract":"<p >One strategy to counter viruses that persistently cause outbreaks is to design molecules that can specifically inhibit an essential multifunctional viral protease. Herein, we present such a strategy using well-established methods to first identify a region present only in viral (but <i>not</i> human) proteases and find peptides that can bind specifically to this “unique” region by maximizing the protease–peptide binding free energy iteratively using single-point mutations starting with the substrate peptide. We applied this strategy to discover pseudosubstrate peptide inhibitors for the multifunctional 2A protease of enterovirus 71 (EV71), a key causative pathogen for hand-foot-and-mouth disease affecting young children, along with coxsackievirus A16. Four peptide candidates predicted to bind EV71 2A protease more tightly than the natural substrate were experimentally validated and found to inhibit protease activity. Furthermore, the crystal structure of the best pseudosubstrate peptide bound to the EV71 2A protease was determined to provide a molecular basis for the observed inhibition. Since the 2A proteases of EV71 and coxsackievirus A16 share nearly identical sequences and structures, our pseudosubstrate peptide inhibitor may prove useful in inhibiting the two key pathogens of hand-foot-and-mouth disease.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"437–449"},"PeriodicalIF":0.0,"publicationDate":"2022-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a6/c7/bg2c00001.PMC10125330.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9357150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergetic Antimicrobial Activity and Mechanism of Clotrimazole-Linked CO-Releasing Molecules","authors":"Sofia S. Mendes,&nbsp;Joana Marques,&nbsp;Edit Mesterházy,&nbsp;Jan Straetener,&nbsp;Melina Arts,&nbsp;Teresa Pissarro,&nbsp;Jorgina Reginold,&nbsp;Anne Berscheid,&nbsp;Jan Bornikoel,&nbsp;Robert M. Kluj,&nbsp;Christoph Mayer,&nbsp;Filipp Oesterhelt,&nbsp;Sofia Friães,&nbsp;Beatriz Royo,&nbsp;Tanja Schneider,&nbsp;Heike Brötz-Oesterhelt*,&nbsp;Carlos C. Romão* and Lígia M. Saraiva*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00007","DOIUrl":"10.1021/acsbiomedchemau.2c00007","url":null,"abstract":"<p >Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)₃(2,2′-bipyridyl)(azole)]⁺ display important synergies against several microbes. We carried out a structure–activity relationship study based upon the lead structure of [Mn(CO)₃(Bpy)(Ctz)]⁺ by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO)₃(Bpy)(Ctz)]⁺ is more than the sum of its parts: while precursor [Re(CO)₃(Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO)₃(Bpy)(Ctz)]⁺ is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO)₃(Bpy)(Ctz)]⁺ to <i>Staphylococcus aureus</i> causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate’s activity relative to that of the antibiotic alone.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"419–436"},"PeriodicalIF":0.0,"publicationDate":"2022-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/64/75/bg2c00007.PMC9389576.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40648612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomodulatory Bandage for Accelerated Healing of Diabetic Wounds","authors":"Jayashree Vijaya Raghavan,&nbsp;Vinod Kumar Dorai,&nbsp;Shruthi Ksheera Sagar,&nbsp;Archana Sivaraman,&nbsp;Kalpana S R and Siddharth Jhunjhunwala*,&nbsp;","doi":"10.1021/acsbiomedchemau.1c00063","DOIUrl":"10.1021/acsbiomedchemau.1c00063","url":null,"abstract":"<p >Diabetic foot ulcers are challenging to treat. Current strategies to treat these wounds focus on preventing infection and promoting tissue regrowth but are ineffective in many individuals. Low-grade chronic inflammation is present in individuals with diabetes, and altering the inflammatory responses at the wound site could be an alternate approach to promote healing. We hypothesized that immunomodulation of the wound microenvironment would result in accelerated healing. To test this hypothesis, we began by characterizing the changes in the myeloid cell phenotype in a mouse model [leptin receptor knockout (KO) mouse] that closely mimics the type 2 diabetes condition observed in humans. We observed increased numbers of monocytes and neutrophils in the circulation of the KO mice compared to that in wild-type control mice. We also observed several phenotypic changes in neutrophils from the KO diabetic mice, suggesting low-grade systemic inflammation. Hence, we developed a rapamycin-loaded chitosan scaffold that may be used to modulate immune responses. The use of these immunomodulatory scaffolds at a wound site resulted in accelerated healing compared to the healing using blank scaffolds. In summary, our data suggest that immunomodulation may be a viable strategy to promote the healing of wounds in individuals with diabetes.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"409–418"},"PeriodicalIF":0.0,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/51/3b/bg1c00063.PMC9389529.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9715864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutually Exclusive Interactions of Rifabutin with Spatially Distinct Mycobacterial Cell Envelope Membrane Layers Offer Insights into Membrane-Centric Therapy of Infectious Diseases","authors":"Anjana P. Menon,&nbsp;Wanqian Dong,&nbsp;Tzong-Hsien Lee,&nbsp;Marie-Isabel Aguilar*,&nbsp;Mojie Duan* and Shobhna Kapoor*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00010","DOIUrl":"10.1021/acsbiomedchemau.2c00010","url":null,"abstract":"<p >The mycobacterial cell envelope has spatially resolved inner and outer membrane layers with distinct compositions and membrane properties. However, the functional implication and relevance of this organization remain unknown. Using membrane biophysics and molecular simulations, we reveal a varied interaction profile of these layers with antibiotic Rifabutin, underlined by the structural and chemical makeup of the constituent lipids. The mycobacterial inner membrane displayed the highest partitioning of Rifabutin, which was located exclusively in the lipid head group/interfacial region. In contrast, the drug exhibited specific interaction sites in the head group/interfacial and hydrophobic acyl regions within the outer membrane. Altogether, we show that the design of membrane-active agents that selectively disrupt the mycobacterial outer membrane structure can increase drug uptake and enhance intracellular drug concentrations. Exploiting the mycobacterium-specific membrane–drug interaction profiles, chemotypes consisting of outer membrane-disruptive agents and antitubercular drugs can offer new opportunities for combinational tuberculosis (TB) therapy.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"395–408"},"PeriodicalIF":0.0,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9389580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40648613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery","authors":"Ranju Bansal*,&nbsp; and ,&nbsp;Amruta Suryan,&nbsp;","doi":"10.1021/acsbiomedchemau.1c00071","DOIUrl":"10.1021/acsbiomedchemau.1c00071","url":null,"abstract":"<p >Ever increasing unmet medical requirements of the human race and the continuous fight for survival against variety of diseases give birth to novel molecules through research. As diseases evolve, different strategies are employed to counter the new challenges and to discover safer, more effective, and target-specific therapeutic agents. Among several novel approaches, bioconjugation, in which two chemical moieties are joined together to achieve noticeable results, has emerged as a simple and convenient technique for a medicinal chemist to obtain potent molecules. The steroid system has been extensively used as a privileged scaffold gifted with significantly diversified medicinal properties in the drug discovery and development process. Steroidal molecules are preferred for their rigidness and good ability to penetrate biological membranes. Slight alteration in the basic ring structure results in the formation of steroidal derivatives with a wide range of therapeutic activities. Steroids are not only active as such, conjugating them with various biologically active moieties results in increased lipophilicity, stability, and target specificity with decreased adverse effects. Thus, the steroid nucleus prominently behaves as a biological carrier for small molecules. The steroid bioconjugates offer several advantages such as synergistic activity with fewer side effects due to reduced dose and selective therapy. The steroidal bioconjugates have been widely explored for their usefulness against various disorders and have shown significant utility as anticancer, anti-inflammatory, anticoagulant, antimicrobial, insecticidal/pesticidal, antioxidant, and antiviral agents along with several other miscellaneous activities. This work provides a comprehensive review on the therapeutic progression of steroidal bioconjugates as medicinally active molecules. The review covers potential biological applications of steroidal bioconjugates and would benefit the wider scientific community in their drug discovery endeavors.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"340–369"},"PeriodicalIF":0.0,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1c/d5/bg1c00071.PMC10125316.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9356528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RaS-RiPPs in Streptococci and the Human Microbiome","authors":"Kenzie A. Clark,&nbsp;Leah B. Bushin and Mohammad R. Seyedsayamdost*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00004","DOIUrl":"10.1021/acsbiomedchemau.2c00004","url":null,"abstract":"<p >Radical <i>S</i>-adenosylmethionine (RaS) enzymes have quickly advanced to one of the most abundant and versatile enzyme superfamilies known. Their chemistry is predicated upon reductive homolytic cleavage of a carbon–sulfur bond in cofactor <i>S</i>-adenosylmethionine forming an oxidizing carbon-based radical, which can initiate myriad radical transformations. An emerging role for RaS enzymes is their involvement in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a natural product family that has become known as RaS-RiPPs. These metabolites are especially prevalent in human and mammalian microbiomes because the complex chemistry of RaS enzymes gives rise to correspondingly complex natural products with minimal cellular energy and genomic fingerprint, a feature that is advantageous in microbes with small, host-adapted genomes in competitive environments. Herein, we review the discovery and characterization of RaS-RiPPs from the human microbiome with a focus on streptococcal bacteria. We discuss the varied chemical modifications that RaS enzymes introduce onto their peptide substrates and the diverse natural products that they give rise to. The majority of RaS-RiPPs remain to be discovered, providing an intriguing avenue for future investigations at the intersection of metalloenzymology, chemical ecology, and the human microbiome.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 4","pages":"328–339"},"PeriodicalIF":0.0,"publicationDate":"2022-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a0/d1/bg2c00004.PMC9389541.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40648615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}