ACS Bio & Med Chem Au最新文献

{"title":"A Reverse Transcription Nucleic-Acid-Based Barcoding System for In Vivo Measurement of Lipid Nanoparticle mRNA Delivery","authors":"Kevin C. Wang,&nbsp;Tiana L. Young,&nbsp;Jingan Chen,&nbsp;Shannon N. Tsai,&nbsp;Yue Xu,&nbsp;Andrew J. Varley,&nbsp;Nicholas C. Solek,&nbsp;Fanglin Gong,&nbsp;Rick X. Z. Lu,&nbsp;Basil P. Hubbard and Bowen Li*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0008110.1021/acsbiomedchemau.4c00081","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00081https://doi.org/10.1021/acsbiomedchemau.4c00081","url":null,"abstract":"<p >Lipid nanoparticles (LNPs) are the most extensively validated clinical delivery vehicles for mRNA therapeutics, exemplified by their widespread use in the mRNA COVID-19 vaccines. The pace of lipid nanoparticle (LNP) development for mRNA therapeutics is restricted by the limitations of existing methods for large-scale LNP screening. To address this challenge, we developed Quantitative Analysis of Reverse Transcribed Barcodes (QuART), a novel nucleic-acid-based system for measuring LNP functional delivery in vivo. QuART uses a bacterial retron reverse transcription system to couple functional mRNA delivery into the cytoplasm with a cDNA barcode readout. Our results demonstrate that QuART can be used to identify functional mRNA delivery both in vitro in cell culture and in vivo in mice. Multiplexing of QuART could enable high-throughput screening of LNP formulations, facilitating the rapid discovery of promising LNP candidates for mRNA therapeutics.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"35–41 35–41"},"PeriodicalIF":3.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436346","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 Reverse Transcription Nucleic-Acid-Based Barcoding System for <i>In Vivo</i> Measurement of Lipid Nanoparticle mRNA Delivery.","authors":"Kevin C Wang, Tiana L Young, Jingan Chen, Shannon N Tsai, Yue Xu, Andrew J Varley, Nicholas C Solek, Fanglin Gong, Rick X Z Lu, Basil P Hubbard, Bowen Li","doi":"10.1021/acsbiomedchemau.4c00081","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00081","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) are the most extensively validated clinical delivery vehicles for mRNA therapeutics, exemplified by their widespread use in the mRNA COVID-19 vaccines. The pace of lipid nanoparticle (LNP) development for mRNA therapeutics is restricted by the limitations of existing methods for large-scale LNP screening. To address this challenge, we developed Quantitative Analysis of Reverse Transcribed Barcodes (QuART), a novel nucleic-acid-based system for measuring LNP functional delivery in vivo. QuART uses a bacterial retron reverse transcription system to couple functional mRNA delivery into the cytoplasm with a cDNA barcode readout. Our results demonstrate that QuART can be used to identify functional mRNA delivery both in vitro in cell culture and in vivo in mice. Multiplexing of QuART could enable high-throughput screening of LNP formulations, facilitating the rapid discovery of promising LNP candidates for mRNA therapeutics.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"35-41"},"PeriodicalIF":3.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484059","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":"Antimicrobial Efficacy of 1,2,3-Triazole-Incorporated Indole-Pyrazolone against Drug-Resistant ESKAPE Pathogens: Design and Synthesis.","authors":"Dipti B Upadhyay, Jaydeep A Mokariya, Paras J Patel, Subham G Patel, Mehul P Parmar, Disha P Vala, Febe Ferro, Dhanji P Rajani, Mahesh Narayan, Jyotish Kumar, Sourav Banerjee, Hitendra M Patel","doi":"10.1021/acsbiomedchemau.4c00060","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00060","url":null,"abstract":"<p><p>In the current study, we report the synthesis of novel 4-((1-((1<i>H</i>-1,2,3-triazole-4-yl)methyl)-1<i>H</i>-indol-3-yl)methylene)-5-methyl-2-phenyl-2,4-dihydro-3<i>H</i>-pyrazole-3-one derivatives <b>5a</b>-<b>o</b>. The compounds were prepared through a Knoevenagel condensation reaction and copper-catalyzed azide-alkyne cycloaddition (CuAAC) Click chemistry approach. The synthesized compounds exhibited promising antimicrobial activity against both Gram-positive and Gram-negative bacteria. Compounds <b>5e</b>, <b>5h</b>, and <b>5i</b> displayed potent activity with MIC value <b>10 μg/mL</b> against <i>Acinetobacter baumannii</i>, in comparison to standard drugs chloramphenicol and ampicillin. Compounds <b>5d</b>, <b>5h</b>, <b>5i</b>, <b>5l</b>, <b>5m,</b> and <b>5n</b> exhibited good-to-moderate antifungal activity against <i>Candida albicans</i> and <i>Aspergillus niger</i> equivalent to standard drugs nystatin and fluconazole. In this study, the cytotoxicity profile of a series of compounds was assessed using SHSY-5Y cells. The results indicate that compounds <b>5a</b>-<b>o</b> exhibit no significant cytotoxicity at concentrations up to <b>100 μg/mL</b>, in comparison to both untreated and vehicle control groups. These findings highlight the safety and tolerability of compounds as well as the potential of the synthesized compounds as effective agents against bacterial and fungal infections.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"66-77"},"PeriodicalIF":3.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484043","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":"Antimicrobial Efficacy of 1,2,3-Triazole-Incorporated Indole-Pyrazolone against Drug-Resistant ESKAPE Pathogens: Design and Synthesis","authors":"Dipti B. Upadhyay,&nbsp;Jaydeep A. Mokariya,&nbsp;Paras J. Patel,&nbsp;Subham G. Patel,&nbsp;Mehul P. Parmar,&nbsp;Disha P. Vala,&nbsp;Febe Ferro,&nbsp;Dhanji P. Rajani,&nbsp;Mahesh Narayan,&nbsp;Jyotish Kumar,&nbsp;Sourav Banerjee* and Hitendra M. Patel*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0006010.1021/acsbiomedchemau.4c00060","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00060https://doi.org/10.1021/acsbiomedchemau.4c00060","url":null,"abstract":"<p >In the current study, we report the synthesis of novel 4-((1-((1<i>H</i>-1,2,3-triazole-4-yl)methyl)-1<i>H</i>-indol-3-yl)methylene)-5-methyl-2-phenyl-2,4-dihydro-3<i>H</i>-pyrazole-3-one derivatives <b>5a</b>–<b>o</b>. The compounds were prepared through a Knoevenagel condensation reaction and copper-catalyzed azide–alkyne cycloaddition (CuAAC) Click chemistry approach. The synthesized compounds exhibited promising antimicrobial activity against both Gram-positive and Gram-negative bacteria. Compounds <b>5e</b>, <b>5h</b>, and <b>5i</b> displayed potent activity with MIC value <b>10 μg/mL</b> against <i>Acinetobacter baumannii</i>, in comparison to standard drugs chloramphenicol and ampicillin. Compounds <b>5d</b>, <b>5h</b>, <b>5i</b>, <b>5l</b>, <b>5m,</b> and <b>5n</b> exhibited good-to-moderate antifungal activity against <i>Candida albicans</i> and <i>Aspergillus niger</i> equivalent to standard drugs nystatin and fluconazole. In this study, the cytotoxicity profile of a series of compounds was assessed using SHSY-5Y cells. The results indicate that compounds <b>5a</b>–<b>o</b> exhibit no significant cytotoxicity at concentrations up to <b>100 μg/mL</b>, in comparison to both untreated and vehicle control groups. These findings highlight the safety and tolerability of compounds as well as the potential of the synthesized compounds as effective agents against bacterial and fungal infections.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"66–77 66–77"},"PeriodicalIF":3.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436040","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":"Cation Pretreatment Enables the Saline Stability of a Near-Infrared Sensor for Dopamine.","authors":"Xuewen Liu, Jing Chen, Hanxuan Wang, Benjamin Lambert, Ardemis A Boghossian","doi":"10.1021/acsbiomedchemau.4c00094","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00094","url":null,"abstract":"<p><p>Single-walled carbon nanotubes (SWCNTs) are wrapped with single-stranded DNA (ssDNA) to create near-infrared (NIR-II) fluorescent sensors for diverse analytes. However, the interaction between the negatively charged backbone of ssDNA and cations in biological saline alters fluorescence unpredictably. This susceptibility limits the application of these sensors in biological media. To address this limitation, this study develops a cation-pretreatment strategy that quenches the baseline fluorescence of ssDNA-SWCNTs to enable turn-on responses that are selectively triggered by analytes in saline. An initial screening of Na⁺, K⁺, Mg²⁺, Ca²⁺, and Al³⁺ pretreatments of gel-encapsulated (AT)₁₅-SWCNTs reveals that Al³⁺ pretreatment induces a stable quenching of fluorescence that is reversible only on Al³⁺ chelation or precipitation. We apply this Al³⁺ pretreatment to develop a saline-resilient, near-infrared sensor for dopamine. The Al³⁺-treated (AT)₁₅-SWCNTs show a concentration- and chirality-dependent fluorescence response over a dynamic range of 1 nM and 10 μM dopamine, achieving a 110-fold increase in the turn-on response to 10 mM dopamine in buffered saline compared with the untreated (AT)₁₅-SWCNTs. Further study of the effects of pH and different salts on the dopamine response suggests a mechanism that relies on competing trivalent cations and negative DNA phosphate interactions. These interactions lay the framework for saline-resilient optical sensors that exploit DNA as a charged-based actuator for modulating the exciton dynamics and controlling the SWCNT fluorescence.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"166-174"},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484050","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":"Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (M^pro) with Noncovalent Preclinical Candidate, Mpro61.","authors":"Jessica R Kenneson, Christina Papini, Su Tang, Kathy Huynh, Chun-Hui Zhang, William L Jorgensen, Karen S Anderson","doi":"10.1021/acsbiomedchemau.4c00109","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00109","url":null,"abstract":"<p><p>SARS-CoV-2 M^pro inhibitors, such as nirmatrelvir, have proven efficacy in clinical use. Nirmatrelvir was developed in a target-based approach against wild-type M^pro, with the anticipation that prolonged usage may cause enrichment of drug-resistant mutations and persistence of COVID infections. Although globally prevalent drug-resistant mutations have not yet been observed, individual cases have recently been reported among patients following treatment with Paxlovid-a formulation of nirmatrelvir. Mutations E166V and E166A have been detected in these drug-resistant clinical isolates, consistent with predictions from <i>in vitro</i> viral passage experiments and therefore necessitate ongoing drug development. In this study, we selected seven M^pro variants (T21I, L50F, E166V, A173V, T190I, E166V/L50F, and A173V/L50F), which have been repeatedly found in viral passage experiments. We investigated their kinetic and structural properties, as well as resistance level to M^pro inhibitors: nirmatrelvir, GC376-a similar peptidomimetic for feline COVID infections, and our in-house-developed nonpeptidomimetic inhibitor Mpro61. Mpro61 maintains potency against the single variants (except for E166V) and the A173/L50F double variant, with <i>K</i> _i values similar to those of the wild type. In contrast, while nirmatrelvir and GC376 were still effective against the A173V/L50F double variant, their <i>K</i> _i values significantly increased up to 10-fold. None of the inhibitors appeared to be potent against E166V-containing variants. Our structural analysis revealed a significant movement of Ser1 residue in all E166V-containing variants in the presence or absence of an inhibitor. The new orientation of the Ser1 suggested potential strategies for medicinal chemistry modifications of Mpro61 to enhance hydrogen-bonding interactions between these variants and Mpro61 derivatives. These studies provide critical insights into guiding the future design of additional Mpro61 derivatives that would potentially inhibit variants with the pan-drug-resistant E166V mutation.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"215-226"},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484070","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":"Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (Mpro) with Noncovalent Preclinical Candidate, Mpro61","authors":"Jessica R. Kenneson,&nbsp;Christina Papini,&nbsp;Su Tang,&nbsp;Kathy Huynh,&nbsp;Chun-Hui Zhang,&nbsp;William L. Jorgensen and Karen S. Anderson*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0010910.1021/acsbiomedchemau.4c00109","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00109https://doi.org/10.1021/acsbiomedchemau.4c00109","url":null,"abstract":"<p >SARS-CoV-2 M^pro inhibitors, such as nirmatrelvir, have proven efficacy in clinical use. Nirmatrelvir was developed in a target-based approach against wild-type M^pro, with the anticipation that prolonged usage may cause enrichment of drug-resistant mutations and persistence of COVID infections. Although globally prevalent drug-resistant mutations have not yet been observed, individual cases have recently been reported among patients following treatment with Paxlovid─a formulation of nirmatrelvir. Mutations E166V and E166A have been detected in these drug-resistant clinical isolates, consistent with predictions from <i>in vitro</i> viral passage experiments and therefore necessitate ongoing drug development. In this study, we selected seven M^pro variants (T21I, L50F, E166V, A173V, T190I, E166V/L50F, and A173V/L50F), which have been repeatedly found in viral passage experiments. We investigated their kinetic and structural properties, as well as resistance level to M^pro inhibitors: nirmatrelvir, GC376─a similar peptidomimetic for feline COVID infections, and our in-house-developed nonpeptidomimetic inhibitor Mpro61. Mpro61 maintains potency against the single variants (except for E166V) and the A173/L50F double variant, with <i>K</i>_i values similar to those of the wild type. In contrast, while nirmatrelvir and GC376 were still effective against the A173V/L50F double variant, their <i>K</i>_i values significantly increased up to 10-fold. None of the inhibitors appeared to be potent against E166V-containing variants. Our structural analysis revealed a significant movement of Ser1 residue in all E166V-containing variants in the presence or absence of an inhibitor. The new orientation of the Ser1 suggested potential strategies for medicinal chemistry modifications of Mpro61 to enhance hydrogen-bonding interactions between these variants and Mpro61 derivatives. These studies provide critical insights into guiding the future design of additional Mpro61 derivatives that would potentially inhibit variants with the pan-drug-resistant E166V mutation.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"215–226 215–226"},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435947","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":"Cation Pretreatment Enables the Saline Stability of a Near-Infrared Sensor for Dopamine","authors":"Xuewen Liu,&nbsp;Jing Chen,&nbsp;Hanxuan Wang,&nbsp;Benjamin Lambert and Ardemis A. Boghossian*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0009410.1021/acsbiomedchemau.4c00094","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00094https://doi.org/10.1021/acsbiomedchemau.4c00094","url":null,"abstract":"<p >Single-walled carbon nanotubes (SWCNTs) are wrapped with single-stranded DNA (ssDNA) to create near-infrared (NIR-II) fluorescent sensors for diverse analytes. However, the interaction between the negatively charged backbone of ssDNA and cations in biological saline alters fluorescence unpredictably. This susceptibility limits the application of these sensors in biological media. To address this limitation, this study develops a cation-pretreatment strategy that quenches the baseline fluorescence of ssDNA-SWCNTs to enable turn-on responses that are selectively triggered by analytes in saline. An initial screening of Na⁺, K⁺, Mg²⁺, Ca²⁺, and Al³⁺ pretreatments of gel-encapsulated (AT)₁₅-SWCNTs reveals that Al³⁺ pretreatment induces a stable quenching of fluorescence that is reversible only on Al³⁺ chelation or precipitation. We apply this Al³⁺ pretreatment to develop a saline-resilient, near-infrared sensor for dopamine. The Al³⁺-treated (AT)₁₅-SWCNTs show a concentration- and chirality-dependent fluorescence response over a dynamic range of 1 nM and 10 μM dopamine, achieving a 110-fold increase in the turn-on response to 10 mM dopamine in buffered saline compared with the untreated (AT)₁₅-SWCNTs. Further study of the effects of pH and different salts on the dopamine response suggests a mechanism that relies on competing trivalent cations and negative DNA phosphate interactions. These interactions lay the framework for saline-resilient optical sensors that exploit DNA as a charged-based actuator for modulating the exciton dynamics and controlling the SWCNT fluorescence.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"166–174 166–174"},"PeriodicalIF":3.8,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435942","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":"Probing the Limits of Reactant Concentration and Volume in Primitive Polyphenyllactate Synthesis and Microdroplet Assembly Processes","authors":"Mahendran Sithamparam,&nbsp;Rehana Afrin,&nbsp;Navaniswaran Tharumen,&nbsp;Ming-Jing He,&nbsp;Chen Chen,&nbsp;Ruiqin Yi,&nbsp;Po-Hsiang Wang,&nbsp;Tony Z. Jia* and Kuhan Chandru*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0008210.1021/acsbiomedchemau.4c00082","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00082https://doi.org/10.1021/acsbiomedchemau.4c00082","url":null,"abstract":"<p >Polyester microdroplets have been investigated as primitive protocell models that can exhibit relevant primitive functions such as biomolecule segregation, coalescence, and salt uptake. Such microdroplets assemble after dehydration synthesis of alpha-hydroxy acid (αHA) monomers, commonly available on early Earth, via heating at mild temperatures, followed by rehydration in aqueous media. αHAs, in particular, are also ubiquitous in biology, participating in a variety of biochemical processes such as metabolism, suggesting the possible strong link between primitive and modern αHA-based processes. Although some primitive αHA polymerization conditions have been probed previously, including monomer chirality and reaction temperature, relevant factors pertaining to early Earth’s local environmental conditions that would likely affect primitive αHA polymerization are yet to be fully investigated. Hence, probing the entire breadth of possible conditions that could promote primitive αHA polymerization is required to understand the plausibility of polyester microdroplet assembly on early Earth at the origin of life. In particular, there are numerous aqueous environments available on early Earth that could have resulted in varying volumes and concentrations of αHA accumulation, which would have affected subsequent αHA polymerization reactions. Similarly, there were likely varying levels of salt in the various aqueous prebiotic solutions, such as in the ocean, lakes, and small pools, that may have affected primitive reactions. Here, we probe the limits of the dehydration synthesis and subsequent membraneless microdroplet (MMD) assembly of phenyllactic acid (PA), a well-studied αHA relevant to both biology and prebiotic chemistry, with respect to reactant concentration and volume and salinity through mass spectrometry- and microscopy-based observations. Our study showed that polymerization and subsequent microdroplet assembly of PA appear robust even at low reactant concentrations, smaller volumes, and higher salinities than those previously tested. This indicates that PA-polyester and its microdroplets are very much viable under a wide variety of conditions, thus more likely participating in prebiotic chemistries at the origins of life.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"131–142 131–142"},"PeriodicalIF":3.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436303","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":"Probing the Limits of Reactant Concentration and Volume in Primitive Polyphenyllactate Synthesis and Microdroplet Assembly Processes.","authors":"Mahendran Sithamparam, Rehana Afrin, Navaniswaran Tharumen, Ming-Jing He, Chen Chen, Ruiqin Yi, Po-Hsiang Wang, Tony Z Jia, Kuhan Chandru","doi":"10.1021/acsbiomedchemau.4c00082","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00082","url":null,"abstract":"<p><p>Polyester microdroplets have been investigated as primitive protocell models that can exhibit relevant primitive functions such as biomolecule segregation, coalescence, and salt uptake. Such microdroplets assemble after dehydration synthesis of alpha-hydroxy acid (αHA) monomers, commonly available on early Earth, via heating at mild temperatures, followed by rehydration in aqueous media. αHAs, in particular, are also ubiquitous in biology, participating in a variety of biochemical processes such as metabolism, suggesting the possible strong link between primitive and modern αHA-based processes. Although some primitive αHA polymerization conditions have been probed previously, including monomer chirality and reaction temperature, relevant factors pertaining to early Earth's local environmental conditions that would likely affect primitive αHA polymerization are yet to be fully investigated. Hence, probing the entire breadth of possible conditions that could promote primitive αHA polymerization is required to understand the plausibility of polyester microdroplet assembly on early Earth at the origin of life. In particular, there are numerous aqueous environments available on early Earth that could have resulted in varying volumes and concentrations of αHA accumulation, which would have affected subsequent αHA polymerization reactions. Similarly, there were likely varying levels of salt in the various aqueous prebiotic solutions, such as in the ocean, lakes, and small pools, that may have affected primitive reactions. Here, we probe the limits of the dehydration synthesis and subsequent membraneless microdroplet (MMD) assembly of phenyllactic acid (PA), a well-studied αHA relevant to both biology and prebiotic chemistry, with respect to reactant concentration and volume and salinity through mass spectrometry- and microscopy-based observations. Our study showed that polymerization and subsequent microdroplet assembly of PA appear robust even at low reactant concentrations, smaller volumes, and higher salinities than those previously tested. This indicates that PA-polyester and its microdroplets are very much viable under a wide variety of conditions, thus more likely participating in prebiotic chemistries at the origins of life.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"131-142"},"PeriodicalIF":3.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484117","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}