Iterative Catalyst-Controlled Diastereoselective Matteson Homologations Enables the Selective Synthesis of Benzestrol Isomers.

We report the development of an iterative Matteson homologation reaction with catalyst-controlled diastereoselectivity through the design of a new catalyst. This reaction was applied to the selective synthesis of each stereoisomer of benzestrol, a bioactive compound with estrogenic activity featuring three contiguous stereocenters. The different stereoisomers were assayed to determine their binding affinity for the estrogen receptor α (ERα), and the absolute configuration of the compound having uniquely high activity was determined. This research lays a framework for the catalytic synthesis and study of complete stereoisomeric sets of other bioactive molecules and chemical probes containing contiguous stereocenters.

Fertility protection during chemotherapy treatment by boosting the NAD(P)+ metabolome.

Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

Chromatin remodellers as therapeutic targets.

Large-scale cancer genome sequencing studies have revealed that chromatin regulators are frequently mutated in cancer. In particular, more than 20% of cancers harbour mutations in genes that encode subunits of SWI/SNF (BAF) chromatin remodelling complexes. Additional links of SWI/SNF complexes to disease have emerged with the findings that some oncogenes drive transformation by co-opting SWI/SNF function and that germline mutations in select SWI/SNF subunits are the basis of several neurodevelopmental disorders. Other chromatin remodellers, including members of the ISWI, CHD and INO80/SWR complexes, have also been linked to cancer and developmental disorders. Consequently, therapeutic manipulation of SWI/SNF and other remodelling complexes has become of great interest, and drugs that target SWI/SNF subunits have entered clinical trials. Genome-wide perturbation screens in cancer cell lines with SWI/SNF mutations have identified additional synthetic lethal targets and led to further compounds in clinical trials, including one that has progressed to FDA approval. Here, we review the progress in understanding the structure and function of SWI/SNF and other chromatin remodelling complexes, mechanisms by which SWI/SNF mutations cause cancer and neurological diseases, vulnerabilities that arise because of these mutations and efforts to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.

Technical considerations for isolated limb perfusion: A consensus paper.

BACKGROUND: Isolated limb perfusion (ILP) is a well-established surgical procedure for the administration of high dose chemotherapy to a limb for the treatment of advanced extremity malignancy. Although the technique of ILP was first described over 60 years ago, ILP is utilised in relatively few specialist centres, co-located with tertiary or quaternary cancer centres. The combination of high dose cytotoxic chemotherapy and the cytokine tumour necrosis factor alpha (TNFα), mandates leakage monitoring to prevent potentially serious systemic toxicity. Since the procedure is performed at relatively few specialist centres, an ILP working group was formed with the aim of producing technical consensus guidelines for the procedure to streamline practice and to provide guidance for new centres commencing the technique. METHODS: Between October 2021 and October 2023 a series of face to face online and hybrid meetings were held in which a modified Delphi process was used to develop a unified consensus document. After each meeting the document was modified and recirculated and then rediscussed at subsequent meeting until a greater than 90% consensus was achieved in all recommendations. RESULTS: The completed consensus document comprised 23 topics in which greater than 90% consensus was achieved, with 83% of recommendations having 100% consensus across all members of the working group. The consensus recommendations covered all areas of the surgical procedure including pre-operative assessment, drug dosing and administration, perfusion parameters, hyperthermia, leakage monitoring and theatre logistics, practical surgical strategies and also post-operative care, response evaluation and staff training. CONCLUSION: We present the first joint expert-based consensus statement with respect to the technical aspects of ILP that can serve as a reference point for both existing and new centres in providing ILP.

Multiplatform High-Definition Ion Mobility Separations of the Largest Epimeric Peptides.

Ion mobility spectrometry (IMS) coupled to mass spectrometry (MS) has become a versatile tool to fractionate complex mixtures, distinguish structural isomers, and elucidate molecular geometries. Along with the whole MS field, IMS/MS advances to ever larger species. A topical proteomic problem is the discovery and characterization of d-amino acid-containing peptides (DAACPs) that are critical to neurotransmission and toxicology. Both linear IMS and FAIMS previously disentangled d/l epimers with up to ∼30 residues. In the first study using all three most powerful IMS methodologies─trapped IMS, cyclic IMS, and FAIMS─we demonstrate baseline resolution of the largest known d/l peptides (CHH from Homarus americanus with 72 residues) with a dynamic range up to 100. This expands FAIMS analyses of isomeric modified peptides, especially using hydrogen-rich buffers, to the ∼50-100 residue range of small proteins. The spectra for d and l are unprecedentedly strikingly similar except for a uniform shift of the separation parameter, indicating the conserved epimer-specific structural elements across multiple charge states and conformers. As the interepimer resolution tracks the average for smaller DAACPs, the IMS approaches could help search for yet larger DAACPs. The a priori method to calibrate cyclic (including multipass) IMS developed here may be broadly useful.

Hydrogen Storage with Aluminum Formate, ALF: Experimental, Computational, and Technoeconomic Studies.

Long-duration storage of hydrogen is necessary for coupling renewable H2 with stationary fuel cell power applications. In this work, aluminum formate (ALF), which adopts the ReO3-type structure, is shown to have remarkable H2 storage performance at non-cryogenic (>120 K) temperatures and low pressures. The most promising performance of ALF is found between 120 K and 160 K and at 10 bar to 20 bar. The study illustrates H2 adsorption performance of ALF over the 77 K to 296 K temperature range using gas isotherms, in situ neutron powder diffraction, and DFT calculations, as well as technoeconomic analysis (TEA), illustrating ALF's competitive performance for long-duration storage versus compressed hydrogen and leading metal-organic frameworks. In the TEA, it is shown that ALF's storage capacity, when combined with a temperature/pressure swing process, has advantages versus compressed H2 at a fraction of the pressure (15 bar versus 350 bar). Given ALF's performance in the 10 bar to 20 bar regime under moderate cooling, it is particularly promising for use in safe storage systems serving fuel cells.

A Systematic Review of Microwave Ablation for Colorectal Pulmonary Metastases.

BACKGROUND/AIM: Pulmonary metastases are the second most common site of metastasis in colorectal cancer after the liver, and microwave ablation (MWA) for its treatment has grown in popularity in patients who are not suitable for pulmonary metastatectomy. However, its long-term efficacy remains unknown. MATERIALS AND METHODS: A systematic review was conducted in July 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using PubMed, EMBASE, Scopus, and Cochrane databases. Studies adopting MWA for colorectal cancer pulmonary metastases were included. RESULTS: A total of 488 lesions were ablated in 230 patients across eight studies. The median duration of ablation was 10 minutes. The mean length of stay in hospital was 2.3 days. Complications included pneumothorax in 128 (52%) patients; pneumonia, which occurred in 4 (1.7%) patients, and pulmonary haemorrhage in 23 (10.0%) patients. Complete remission was achieved in 85 (37.0%) patients, local control was achieved in 103 (44.8%) patients, and residual or progressive disease remained in 85 (37.0%). Survival post ablation at 1 year was 89.2% and at 3 years was 40.3%. Post-ablation disease-free survival was 43.2% at 3 years. CONCLUSION: MWA is an alternative treatment for pulmonary metastases of colorectal cancer. It has competitive theoretical properties and local recurrence rate compared to radiofrequency ablation.

Plastid dsRNA transgenes trigger phased small RNA-based gene silencing of nuclear-encoded genes.

Plastid transformation technology has been widely used to express traits of potential commercial importance, though the technology has been limited to traits that function while sequestered in the organelle. Prior research indicates that plastid contents can escape from the organelle, suggesting a possible mechanism for engineering plastid transgenes to function in other cellular locations. To test this hypothesis, we created tobacco (Nicotiana tabacum cv. Petit Havana) plastid transformants that express a fragment of the nuclear-encoded Phytoene desaturase (PDS) gene capable of catalyzing post-transcriptional gene silencing if RNA escapes into the cytoplasm. We found multiple lines of direct evidence that plastid-encoded PDS transgenes affect nuclear PDS gene silencing: knockdown of the nuclear-encoded PDS mRNA and/or its apparent translational inhibition, biogenesis of 21-nucleotide (nt) phased small interfering RNAs (phasiRNAs), and pigment-deficient plants. Furthermore, plastid-expressed dsRNA with no cognate nuclear-encoded pairing partner also produced abundant 21-nt phasiRNAs in the cytoplasm, demonstrating that a nuclear-encoded template is not required for siRNA biogenesis. Our results indicate that RNA escape from plastids to the cytoplasm occurs generally, with functional consequences that include entry into the gene silencing pathway. Furthermore, we uncover a method to produce plastid-encoded traits with functions outside of the organelle and open additional fields of study in plastid development, compartmentalization, and small RNA biogenesis.

Exclusive Recognition of CO2 from Hydrocarbons by Aluminum Formate with Hydrogen-Confined Pore Cavities.

Exclusive capture of carbon dioxide (CO2) from hydrocarbons via adsorptive separation is an important technology in the petrochemical industry, especially for acetylene (C2H2) production. However, the physicochemical similarities between CO2 and C2H2 hamper the development of CO2-preferential sorbents, and CO2 is mainly discerned via C recognition with low efficiency. Here, we report that the ultramicroporous material Al(HCOO)3, ALF, can exclusively capture CO2 from hydrocarbon mixtures, including those containing C2H2 and CH4. ALF shows a remarkable CO2 capacity of 86.2 cm3 g-1 and record-high CO2/C2H2 and CO2/CH4 uptake ratios. The inverse CO2/C2H2 separation and exclusive CO2 capture performance from hydrocarbons are validated via adsorption isotherms and dynamic breakthrough experiments. Notably, the hydrogen-confined pore cavities with appropriate dimensional size provide an ideal pore chemistry to specifically match CO2 via a hydrogen bonding mechanism, with all hydrocarbons rejected. This molecular recognition mechanism is unveiled by in situ Fourier-transform infrared spectroscopy, X-ray diffraction studies, and molecular simulations.

Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).

The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. We describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CLpro or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were >50 µM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an α-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1eand1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.

Noncryogenic Air Separation Using Aluminum Formate Al(HCOO)3 (ALF).

Separating oxygen from air to create oxygen-enriched gas streams is a process that is significant in both industrial and medical fields. However, the prominent technologies for creating oxygen-enriched gas streams are both energy and infrastructure intensive as they use cryogenic temperatures or materials that adsorb N2 from air. The latter method is less efficient than the methods that adsorb O2 directly. Herein, we show, via a combination of gas adsorption isotherms, gas breakthrough experiments, neutron and synchrotron X-ray powder diffraction, Raman spectroscopy, and computational studies, that the metal-organic framework, Al(HCOO)3 (ALF), which is easily prepared at low cost from commodity chemicals, exhibits substantial O2 adsorption and excellent time-dependent O2/N2 selectivity in a range of 50-125 near dry ice/solvent (≈190 K) temperatures. The effective O2 adsorption with ALF at ≈190 K and ≈0.21 bar (the partial pressure of O2 in air) is ≈1.7 mmol/g, and at ice/salt temperatures (≈250 K), it is ≈0.3 mmol/g. Though the kinetics for full adsorption of O2 near 190 K are slower than at temperatures nearer 250 K, the kinetics for initial O2 adsorption are fast, suggesting that O2 separation using ALF with rapid temperature swings at ambient pressures is a potentially viable choice for low-cost air separation applications. We also present synthetic strategies for improving the kinetics of this family of compounds, namely, via Al/Fe solid solutions. To the best of our knowledge, ALF has the highest O2/N2 sorption selectivity among MOF adsorbents without open metal sites as verified by co-adsorption experiments..

The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer's disease.

Introduction: The disintegrin and metalloproteinase 17 (ADAM17) exhibits α-secretase activity, whereby it can prevent the production of neurotoxic amyloid precursor protein-α (APP). ADAM17 is abundantly expressed in vascular endothelial cells and may act to regulate vascular homeostatic responses, including vasomotor function, vascular wall morphology, and formation of new blood vessels. The role of vascular ADAM17 in neurodegenerative diseases remains poorly understood. Here, we hypothesized that cerebrovascular ADAM17 plays a role in the pathogenesis of Alzheimer's disease (AD). Methods and results: We found that 9-10 months old APP/PS1 mice with b-amyloid accumulation and short-term memory and cognitive deficits display a markedly reduced expression of ADAM17 in cerebral microvessels. Systemic delivery and adeno-associated virus (AAV)-mediated re-expression of ADAM17 in APP/PS1 mice improved cognitive functioning, without affecting b-amyloid plaque density. In isolated and pressurized cerebral arteries of APP/PS1 mice the endothelium-dependent dilation to acetylcholine was significantly reduced, whereas the vascular smooth muscle-dependent dilation to the nitric oxide donor, sodium nitroprusside was maintained when compared to WT mice. The impaired endothelium-dependent vasodilation of cerebral arteries in APP/PS1 mice was restored to normal level by ADAM17 re-expression. The cerebral artery biomechanical properties (wall stress and elasticity) and microvascular network density was not affected by ADAM17 re-expression in the APP/PS1 mice. Additionally, proteomic analysis identified several differentially expressed molecules involved in AD neurodegeneration and neuronal repair mechanisms that were reversed by ADAM17 re-expression. Discussion: Thus, we propose that a reduced ADAM17 expression in cerebral microvessels impairs vasodilator function, which may contribute to the development of cognitive dysfunction in APP/PS1 mice, and that ADAM17 can potentially be targeted for therapeutic intervention in AD.

Using a Capsular Tension Ring (CTR) Inserter for CTR Explantation in Cases of Posteriorly Dislocated Intraocular Lens-CTR-Capsule Complex.

PURPOSE: Explantation of a dislocated capsular tension ring (CTR) from the vitreous cavity can be challenging, typically requiring a bimanual hand-shake technique or cutting the CTR into segments. We present three cases of dislocated intraocular lens (IOL)-CTR-capsule complexes in which CTRs were explanted efficiently and safely by using a CTR inserter (CTR-I) through a clear corneal incision. METHODS: Retrospective case series. RESULTS: Capsular tension rings were successfully explanted by freeing the eyelet of the CTR from the capsule, engaging it with the CTR-I hook and retracting the CTR into the device's shaft while maintaining the entire IOL-CTR-capsule complex in a safe position behind the iris plane. No complications of the procedure were observed in all three cases. All patients had subsequent uneventful IOL exchange through sutureless scleral fixation during the same surgery. CONCLUSION: The CTR inserter provides a simple and efficient approach to CTR removal from IOL-CTR-capsule complexes dislocated into the vitreous cavity. Greater awareness of this technique among providers is needed.

Aluminum formate, Al(HCOO)3: An earth-abundant, scalable, and highly selective material for CO2 capture.

A combination of gas adsorption and gas breakthrough measurements show that the metal-organic framework, Al(HCOO)3 (ALF), which can be made inexpensively from commodity chemicals, exhibits excellent CO2 adsorption capacities and outstanding CO2/N2 selectivity that enable it to remove CO2 from dried CO2-containing gas streams at elevated temperatures (323 kelvin). Notably, ALF is scalable, readily pelletized, stable to SO2 and NO, and simple to regenerate. Density functional theory calculations and in situ neutron diffraction studies reveal that the preferential adsorption of CO2 is a size-selective separation that depends on the subtle difference between the kinetic diameters of CO2 and N2. The findings are supported by additional measurements, including Fourier transform infrared spectroscopy, thermogravimetric analysis, and variable temperature powder and single-crystal x-ray diffraction.

Major vascular reconstruction in colorectal adenocarcinoma and retroperitoneal sarcoma: A retrospective study of safety and margins in a tertiary referral centre.

BACKGROUND: The role of en bloc vascular resection and reconstruction (EVRR) is controversial in colorectal adenocarcinoma (CRC), but well-established in retroperitoneal sarcoma (RPS). Sparse data exists regarding these complex procedures. METHODS: Patients undergoing curative intent EVRR for advanced CRC and RPS between 2014 and 2021 at a tertiary centre were included. Morbidity, margins, recurrence, and survival were evaluated. RESULTS: 24 patients underwent EVRR with 48 reconstructions (11 CRC and 13 RPS). For CRC, 100% of patients underwent Iliac system reconstructions. For RPS, inferior vena cava reconstructions were the most common (69.2%). There were 2 arterial and 1 venous graft thromboses. Primary graft patency was 89.4% arterial and 93.1% venous, while secondary patency was 100% arterial and 96.5% venous at last follow up. 1 venous and 1 arterial graft required reoperation for bleeding. There were no compromised limbs. Major complications occurred in 6 patients (25.0%) with no observed difference between CRC and RPS (OR 0.43 95%CI[0.60,3.19], P = 0.41). R1 margins occurred 1 CRC (90.9%) and 3 RPS (76.9%), with no R2 resections. All vascular resection margins were clear. There were 6 CRC (50%) and 4 RPS (33.3%) recurrences. Median recurrence time was 20.9 months for CRC and 'not yet reached' for RPS. Median follow-up was 19.4 months for CRC and 21.4 months for RPS. CONCLUSION: EVRR for locally advanced CRC or RPS is safe and achieves favorable R0 resection rates. CRC patients with major vascular invasion can still be considered for curative intent surgery. Larger cohorts with longer follow up are needed to assess oncologic outcomes.

Effect of degeneration on bone mineral density, trabecular bone score and CT Hounsfield unit measurements in a spine surgery patient population.

This study investigated the impact of spinal degeneration on bone mineral density (BMD), trabecular bone score (TBS), and CT Hounsfield units in an at-risk population. We found that BMD was increased by degeneration, whereas TBS and HU were unaffected. These findings support that TBS is not adversely affected by spinal degeneration. INTRODUCTION: This study evaluated the impact of spinal degeneration on BMD and TBS measured by dual-energy x-ray absorptiometry (DXA) and on CT HU in a spine surgery patient population. METHODS: A retrospective study of 63 patients referred for consideration of spine surgery or with history of spine surgery was performed. Patients were included if a DXA scan and a CT containing the lumbar spine were obtained within 18 months of each other. DXA data were collected and analyzed by vertebral level. Individual vertebrae were assessed for degenerative changes by qualitative evaluation of the anterior and posterior elements using CT. Degeneration scores were compared to BMD T-scores, TBS and CT HU at individual vertebral levels L1-4, and after applying International Society for Clinical Densitometry (ISCD) criteria for excluding vertebrae from diagnostic consideration. RESULTS: Mean patient age and BMI were 67.2 years and 27.8 kg/m2, respectively; 79.4% were female. Mean (SD) lowest T-scores of the hip, spine, and lowest overall T-score were - 1.3 (1.4), - 1.7 (0.9), and - 1.9 (1.0), respectively. Osteoporosis was present by T-score in 38% and osteopenia in 52%; 10% had a history of osteoporotic fracture. The mean degeneration score of individual vertebrae was 4.1 on a 0-6 scale. T-score correlated moderately with degeneration score (Spearman's rho 0.484, p < 0.001), whereas TBS and HU were unrelated. ISCD excluded vertebrae had a higher degeneration score than included vertebrae (p = < 0.001). CONCLUSIONS: In a spine surgery population, TBS and CT HU values are unrelated to degeneration score and thus appear unaffected by lumbar vertebral degenerative changes. Additionally, these data support the ISCD criteria for vertebral exclusion.

Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease.

The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

The COVID-19 pandemic is having a major impact on public health worldwide, and there is an urgent need for the creation of an armamentarium of effective therapeutics, including vaccines, biologics, and small-molecule therapeutics, to combat SARS-CoV-2 and emerging variants. Inspection of the virus life cycle reveals multiple viral- and host-based choke points that can be exploited to combat the virus. SARS-CoV-2 3C-like protease (3CLpro), an enzyme essential for viral replication, is an attractive target for therapeutic intervention, and the design of inhibitors of the protease may lead to the emergence of effective SARS-CoV-2-specific antivirals. We describe herein the results of our studies related to the application of X-ray crystallography, the Thorpe-Ingold effect, deuteration, and stereochemistry in the design of highly potent and nontoxic inhibitors of SARS-CoV-2 3CLpro.

Peritectic phase transition of benzene and acetonitrile into a cocrystal relevant to Titan, Saturn's moon.

Benzene and acetonitrile are two of the most commonly used solvents found in almost every chemical laboratory. Titan is one other place in the solar system that has large amounts of these compounds. On Titan, organic molecules are produced in the atmosphere and carried to the surface where they can mineralize. Here, we report the phase diagram of mixtures of acetonitrile and benzene, and provide an account of the structure and composition of the phases. To mimic the environment on Titan more accurately, we tested the stability of the structure under liquid ethane. The results provide new insights into the structure and stability of potential extraterrestrial minerals. In light of Dragonfly, NASA's upcoming mission to Titan, revisiting the fundamental chemistry of the smallest molecules with modern methods and techniques can have significant contributions to this epochal mission and can open new research directions in chemistry.