SARS-CoV-2 evolution has increased resistance to monoclonal antibodies and first-generation COVID-19 vaccines: Is there a future therapeutic role for soluble ACE2 receptors for COVID-19?

COVID-19 has caused calamitous health, economic and societal consequences. Although several COVID-19 vaccines have received full authorization for use, global deployment has faced political, financial and logistical challenges. The efficacy of first-generation COVID-19 vaccines is waning and breakthrough infections are allowing ongoing transmission and evolution of SARS-CoV-2. Furthermore, COVID-19 vaccine efficacy relies on a functional immune system. Despite receiving three primary doses and three or more heterologous boosters, some immunocompromised patients may not be adequately protected by COVID-19 vaccines and remain vulnerable to severe disease. The evolution of new SARS-CoV-2 variants has also resulted in the rapid obsolescence of monoclonal antibodies. Convalescent plasma from COVID-19 survivors has produced inconsistent results. New drugs such as Paxlovid (nirmatrelvir/ritonavir) are beyond the reach of low- and middle-income countries. With widespread use of Paxlovid, it is likely nirmatrelvir-resistant clades of SARS-CoV-2 will emerge in the future. There is thus an urgent need for new effective anti-SARS-CoV-2 treatments. The in vitro efficacy of soluble ACE2 against multiple SARS-CoV-2 variants including omicron (B.1.1.529), was recently described using a competitive ELISA assay as a surrogate marker for virus neutralization. This indicates soluble wild-type ACE2 receptors are likely to be resistant to viral evolution. Nasal and inhaled treatment with soluble ACE2 receptors has abrogated severe disease in animal models of COVID-19. There is an urgent need for clinical trials of this new class of antiviral therapeutics, which could complement vaccines and Paxlovid.

The autoimmune rheumatological presentation of Common Variable Immunodeficiency Disorders with an overview of genetic testing.

Primary immunodeficiency Disorders (PIDS) are rare, mostly monogenetic conditions which can present to a number of specialties. Although infections predominate in most PIDs, some individuals can manifest autoimmune or inflammatory sequelae as their initial clinical presentation. Identifying patients with PIDs can be challenging, as some can present later in life. This is often seen in patients with Common Variable Immunodeficiency Disorders (CVID), where symptoms can begin in the sixth or even seventh decades of life. Some patients with PIDs including CVID can initially present to rheumatologists with autoimmune musculoskeletal manifestations. It is imperative for these patients to be identified promptly as immunosuppression could lead to life-threatening opportunistic infections in these immunocompromised individuals. These risks could be mitigated by prior treatment with subcutaneous or intravenous (SCIG/IVIG) immunoglobulin replacement or prophylactic antibiotics. Importantly, many of these disorders have an underlying genetic defect. Individualized treatments may be available for the specific mutation, which may obviate or mitigate the need for hazardous broad-spectrum immunosuppression. Identification of the genetic defect has profound implications not only for the patient but also for affected family members, who may be at risk of symptomatic disease following an environmental trigger such as a viral infection. Finally, there may be clinical clues to the underlying PID, such as recurrent infections, the early presentation of severe or multiple autoimmune disorders, as well as a relevant family history. Early referral to a clinical immunologist will facilitate appropriate diagnostic evaluation and institution of treatment such as SCIG/IVIG immunoglobulin replacement. This review comprises three sections; an overview of PIDs, focusing on CVID, secondly genetic testing of PIDs and finally the clinical presentation of these disorders to rheumatologists.

Liposome-enabled bufalin and doxorubicin combination therapy for trastuzumab-resistant breast cancer with a focus on cancer stem cells.

Breast cancer stem cells (BCSCs) play a key role in therapeutic resistance in breast cancer treatments and disease recurrence. This study aimed to develop a combination therapy loaded with pH-sensitive liposomes to kill both BCSCs and the okbulk cancer cells using trastuzumab-sensitive and resistant human epidermal growth factor receptor 2 positive (HER2+) breast cancer cell models. The anti-BCSCs effect and cytotoxicity of all-trans retinoic acid, salinomycin, and bufalin alone or in combination with doxorubicin were compared in HER2+ cell line BT-474 and a validated trastuzumab-resistant cell line, BT-474R. The most potent anti-BCSC agent was selected and loaded into a pH-sensitive liposome system. The effects of the liposomal combination on BCSCs and bulk cancer cells were assessed. Compared with BT-474, the aldehyde dehydrogenase positive BCSC population was elevated in BT-474R (3.9 vs. 23.1%). Bufalin was the most potent agent and suppressed tumorigenesis of BCSCs by ∼50%, and showed strong synergism with doxorubicin in both BT-474 and BT-474R cell lines. The liposomal combination of bufalin and doxorubicin significantly reduced the BCSC population size by 85%, and inhibited both tumorigenesis and self-renewal, although it had little effect on the migration and invasiveness. The cytotoxicity against the bulk cancer cells was also enhanced by the liposomal combination than either formulation alone in both cell lines (p < 0.001). The liposomal bufalin and doxorubicin combination therapy may effectively target both BCSCs and bulk cancer cells for a better outcome in trastuzumab-resistant HER2+ breast cancer.

Challenges for gene editing in common variable immunodeficiency disorders: Current and future prospects.

The original CRISPR Cas9 gene editing system and subsequent innovations offers unprecedented opportunities to correct severe genetic defects including those causing Primary Immunodeficiencies (PIDs). Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic PID in adults and children. Unlike many other PIDs, patients meeting CVID criteria do not have a definable genetic defect and cannot be considered to have an inborn error of immunity (IEI). Patients with a CVID phenotype carrying a causative mutation are deemed to have a CVID-like disorder consequent to an IEI. Patients from consanguineous families often have highly penetrant early-onset autosomal recessive forms of CVID-like disorders. Individuals from non-consanguineous families may have autosomal dominant CVID-like disorders with variable penetrance and expressivity. This essay explores the potential clinical utility as well as the current limitations and risks of gene editing including collateral genotoxicity. In the immediate future the main application of this technology is likely to be the in vitro investigation of epigenetic and polygenic mechanisms, which are likely to underlie many cases of CVID and CVID-like disorders. In the longer-term, the CRISPR Cas9 system and other gene-based therapies could be utilized to treat CVID-like disorders, where the underlying IEI is known.

Phosphatidylcholine-Specific Phospholipase C as a Promising Drug Target.

Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from Bacillus cereus (PC-PLCBc). Nonetheless, there is evidence for PC-PLC activity as a human functional equivalent of its prokaryotic counterpart. Additionally, inhibitors of PC-PLCBc have been developed as potential therapeutic agents. The most notable classes include 2-aminohydroxamic acids, xanthates, N,N'-hydroxyureas, phospholipid analogues, 1,4-oxazepines, pyrido[3,4-b]indoles, morpholinobenzoic acids and univalent ions. However, many medicinal chemistry studies lack evidence for their cellular and in vivo effects, which hampers the progression of the inhibitors towards the clinic. This review outlines the pathological implications of PC-PLC and highlights current progress and future challenges in the development of PC-PLC inhibitors from the literature.

Soluble wild-type ACE2 molecules inhibit newer SARS-CoV-2 variants and are a potential antiviral strategy to mitigate disease severity in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease of 2019 (COVID-19), has caused havoc around the world. While several COVID-19 vaccines and drugs have been authorized for use, these antiviral drugs remain beyond the reach of most low- and middle-income countries. Rapid viral evolution is reducing the efficacy of vaccines and monoclonal antibodies and contributing to the deaths of some fully vaccinated persons. Others with normal immunity may have chosen not to be vaccinated and remain at risk if they contract the infection. Vaccines may not protect some immunodeficient patients from SARS-CoV-2, who are also at increased risk of chronic COVID-19 infection, a dangerous stalemate between the virus and a suboptimal immune response. Intra-host viral evolution could rapidly lead to the selection and dominance of vaccine and monoclonal antibody-resistant clades of SARS-CoV-2. There is thus an urgent need to develop new treatments for COVID-19. The NZACE2-Patari project, comprising modified soluble angiotensin-converting enzyme 2 (ACE2) molecules, seeks to intercept and block SARS-CoV-2 infection of the respiratory mucosa. In vitro data presented here show that soluble wild-type ACE2 molecules retain the ability to effectively block the Spike (S) glycoprotein of SARS-CoV-2 variants including the ancestral Wuhan, delta (B.1.617.2) and omicron (B.1.1.529) strains. This therapeutic strategy may prove effective if implemented early during the nasal phase of the infection and may act synergistically with other antiviral drugs such as Paxlovid to further mitigate disease severity.

Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines.

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25-50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis.

Functionalisation of extracellular vesicles with cyclic-RGDyC potentially for glioblastoma targeted intracellular drug delivery.

With the intrinsic ability to cross the blood-brain barrier, small extracellular vesicles (sEVs) hold promise as endogenous brain-targeted drug delivery nano-platforms for glioblastoma (GBM) treatment. To increase GBM targetability, this study aimed to functionalise sEVs with cyclic arginine-glycine-aspartic acid-tyrosine-cysteine (cRGDyC), a ligand for integrin (αvß3) that is overexpressed in GBM cells. Firstly, the intrinsic cellular uptake of sEVs derived from GBM U87 and pancreatic cancer MIA PaCa-2 cells was investigated on the donor cells. To obtain functionalised sEVs (cRGDyC-sEVs), DSPE-mPEG2000-maleimide was incubated with the selected (U87) sEVs, and cRGDyC was subsequently conjugated to the maleimide groups via a thiol-maleimide coupling reaction. The GBM cell targetability and intracellular trafficking of cRGDyC-sEVs were evaluated on U87 cells by fluorescence and confocal microscopy, using unmodified sEVs as a reference. The cytotoxicity of doxorubicin-loaded vesicles (Dox@sEVs, Dox@cRGDyC-sEVs) was compared with a standard liposome formulation (Dox@Liposomes) and free Dox. Both U87 and MIA PaCa-2 cell-derived sEVs displayed tropism with the former being >4.9-fold more efficient to be internalised into U87. Therefore, the U87-derived sEVs were chosen for GBM-targeting. Approximately 4000 DSPE-mPEG2000-maleimide were inserted onto each sEV with cRGDyC conjugated to the maleimide group. The cell targetability of cRGDyC-sEVs to U87 cells improved 2.4-fold than natural sEVs. Despite their proneness to be colocalised with endosomes/lysosomes, both Dox@sEVs and Dox@cRGDyC-sEVs showed superior cytotoxicity to U87 GBM cells compared to Dox@Liposomes, particularly Dox@cRGDyC-sEVs. Overall, U87-derived sEVs were successufully conjugated with cRGDyC via a PEG linker, and cRGDyC-sEVs were demonstrated to be a potnetial integrin-targeting drug delivery vehicle for GBM treatment. Graphic abstract.

Investigation of 2-phenylimidazo[1,2-a]quinolines as potential antiproliferative agents.

Background: It has been demonstrated that the lead compound 2-phenylimidazo[1,2-a]quinoline 1a selectively inhibits CYP1 enzymes. Additionally, CYP1 inhibition has been linked to inducing antiproliferative effects in various breast cancer cell lines as well as relieving drug resistance caused by CYP1 upregulation. Materials & methods: Herein, 54 novel analogs of 2-phenylimidazo[1,2-a]quinoline 1a have been synthesized with varied substitution on the phenyl and imidazole rings. Antiproliferative testing was conducted using 3H thymidine uptake assays. Results: 2-Phenylimidazo[1,2-a]quinoline 1a and phenyl-substituted analogs 1c (3-OMe), 1n (2,3-napthalene) displayed excellent anti-proliferative activities, demonstrating their potency against cancer cell lines for the first time. Molecular modeling suggested that 1c and 1n bind similarly to 1a in the CYP1 binding site.

Stability of trastuzumab during nanomedicine formulation using SEC-HPLC coupled with polyacrylamide gel electrophoresis.

The anti-HER2 antibody trastuzumab has been proven to be an effective targeting ligand for drug delivery. This study investigates the structural integrity of trastuzumab under different stress factors in formulation development and its long-term stability. A validated size exclusion high performance liquid chromatographic (SEC-HPLC) method was first developed. The stability of trastuzumab (0.21-21 mg/ml) under stress conditions (mechanical, freeze-and-thaw, pH and temperature) and long-term storage in the presence of formulation excipients were monitored for up to 12 months, using both the SEC-HPLC method and sodium-dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The anti-proliferation activity of the reconstituted antibody stored at 4 °C against HER2+ BT-474 breast cells was also monitored over 12 months. The developed SEC-HPLC method was sensitive and accurate. Solutions of trastuzumab were resistant to mechanical stress and repeated freeze-and-thaw; but were unstable under acidic (pH 2.0 and 4.0) and alkaline (pH 10.0 and 12.0) environments. The samples degraded over 5 days at 60 °C, and within 24 h at 75 °C. Low temperature (-80 °C or 4 °C) and low concentration (0.21 mg/ml) favoured the long-term stability. The anti-proliferation activity was conserved at 4 °C for at least 12 months. This study provided valuable stability information in developing trastuzumab involved nano-formulation as well as in clinical settings.

The Rapidly Expanding Genetic Spectrum of Common Variable Immunodeficiency-Like Disorders.

The understanding of common variable immunodeficiency disorders (CVID) is in evolution. CVID was previously a diagnosis of exclusion. New diagnostic criteria have allowed the disorder to be identified with greater precision. With the advent of next-generation sequencing (NGS), it has become apparent that an increasing number of patients with a CVID phenotype have a causative genetic variant. If a pathogenic variant is identified, these patients are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder. In populations where consanguinity is more prevalent, the majority of patients with severe primary hypogammaglobulinemia will have an underlying inborn error of immunity, usually an early-onset autosomal recessive disorder. In nonconsanguineous societies, pathogenic variants are identified in approximately 20% to 30% of patients. These are often autosomal dominant mutations with variable penetrance and expressivity. To add to the complexity of CVID and CVID-like disorders, some genetic variants such as those in TNFSF13B (transmembrane activator calcium modulator cyclophilin ligand interactor) predispose to, or enhance, disease severity. These variants are not causative but can have epistatic (synergistic) interactions with more deleterious mutations to worsen disease severity. This review is a description of the current understanding of genes associated with CVID and CVID-like disorders. This information will assist clinicians in interpreting NGS reports when investigating the genetic basis of disease in patients with a CVID phenotype.

Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9' Derivatisation.

Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9' position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9'-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9' derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9'-hydroxymethyl lead compound.

Selective IgA Deficiency May Be an Underrecognized Risk Factor for Severe COVID-19.

SARS-CoV-2, the agent responsible for COVID-19, has wreaked havoc around the globe. Hundreds of millions of individuals have been infected and well over six million have died from COVID-19. Many COVID-19 survivors have ongoing physical and psychiatric morbidity, which will remain for the rest of their lives. Early in the pandemic, it became apparent that older individuals and those with comorbidities including obesity, diabetes mellitus, coronary artery disease, hypertension, and renal and pulmonary disease were at increased risk of adverse outcomes. It is also clear that some immunodeficient patients, such as those with innate or T cell-immune defects, are at greater risk from COVID-19. Selective IgA deficiency (sIgAD) is generally regarded as a mild disorder in which most patients are asymptomatic because of redundancy in protective immune mechanisms. Recent data indicate that patients with sIgAD may be at high risk of severe COVID-19. SARS-CoV-2 gains entry primarily through the upper respiratory tract mucosa, where IgA has a critical protective role. This may underlie the vulnerability of sIgAD patients to adverse outcomes from COVID-19. This perspective highlights the need for ongoing research into mucosal immunity to improve COVID-19 treatments for patients with sIgAD.

Critical role of diagnostic SARS-CoV-2 T cell assays for immunodeficient patients.

After almost 3 years of intense study, the immunological basis of COVID-19 is better understood. Patients who suffer severe disease have a chaotic, destructive immune response. Many patients with severe COVID-19 produce high titres of non-neutralising antibodies, which are unable to sterilise the infection. In contrast, there is increasing evidence that a rapid, balanced cellular immune response is required to eliminate the virus and mitigate disease severity. In the longer term, memory T cell responses, following infection or vaccination, play a critical role in protection against SARS-CoV-2.Given the pivotal role of cellular immunity in the response to COVID-19, diagnostic T cell assays for SARS-CoV-2 may be of particular value for immunodeficient patients. A diagnostic SARS-CoV-2 T cell assay would be of utility for immunocompromised patients who are unable to produce antibodies or have passively acquired antibodies from subcutaneous or intravenous immunoglobulin (SCIG/IVIG) replacement. In many antibody-deficient patients, cellular responses are preserved. SARS-CoV-2 T cell assays may identify breakthrough infections if reverse transcriptase quantitative PCR (RT-qPCR) or rapid antigen tests (RATs) are not undertaken during the window of viral shedding. In addition to utility in patients with immunodeficiency, memory T cell responses could also identify chronically symptomatic patients with long COVID-19 who were infected early in the pandemic. These individuals may have been infected before the availability of reliable RT-qPCR and RAT tests and their antibodies may have waned. T cell responses to SARS-CoV-2 have greater durability than antibodies and can also distinguish patients with infection from vaccinated individuals.

Impact of Coordination Mode and Ferrocene Functionalization on the Anticancer Activity of N-Heterocyclic Carbene Half-Sandwich Complexes.

The substitution of phenyl rings in established drugs with ferrocenyl moieties has been reported to yield compounds with improved biological activity and alternative modes of action, often involving the formation of reactive oxygen species (ROS). Translating this concept to N-heterocyclic carbene (NHC) complexes, we report here organometallics with a piano-stool structure that feature di- or tridentate ligand systems. The ligands impacted the cytotoxic activity of the NHC complexes, but the coordination modes seemed to have a limited influence, which may be related to the propensity of forming the same species in solution. In general, the stability of the complexes in an aqueous environment and their reactivity to selected biomolecules were largely dominated by the nature of the metal center. While the complexes promoted the formation of ROS, the levels did not correlate with their cytotoxic activity. However, the introduction of ferrocenyl moieties had a significant impact on the antiproliferative potency of the complexes and, in particular, some of the ferrocenyl-functionalized compounds yielded IC50 values in the low µM range.

A simple approach to re-engineering small extracellular vesicles to circumvent endosome entrapment.

Small extracellular vesicles (sEVs) have emerged as attractive drug delivery systems. However, the intracellular release of their cargoes is restricted. This study aimed to develop an efficient approach to re-engineer sEVs by hybridisation with pH-sensitive liposomes (PSLs) and investigate their endosome escape potential. MIA PaCa-2 cell-derived sEVs and PSLs were fused via three methods, and fusion efficiency (FE) was measured using a fluorescence resonance energy transfer assay and nanoparticle tracking analysis. Cellular uptake, intracellular trafficking, and cytotoxicity of doxorubicin-loaded vesicles (Dox@hybrids, Dox@sEVs, and Dox@PSLs) were investigated on MIA PaCa-2 cells. Among the three methods, Ca2+-mediated fusion was the simplest and led to a comparable FE with freeze-thaw method, which was significantly higher than PEG8000-mediated fusion. sEVs were more stable after hybridisation with PSLs. Confocal microscopy revealed that the hybrids internalised more efficiently than natural sEVs. While the internalised Dox@sEVs were primarily co-localised with endo/lysosomes even after 8 h, Dox from Dox@hybrids was found to escape from endosomes by 2 h and homogenously distributed in the cytosol before accumulated at nucleus, corresponding to the in vitro pH-responsive release profile. Consequently, Dox@hybrids enhanced cytotoxicity compared with Dox@sEVs, Dox@PSLs, or free drugs. Overall, the biomimetic nanosystem generated by simple Ca2+-mediated fusion was more stable and demonstrated higher efficiencies of cellular uptake and endosome escape compared to natural sEVs.

In vitro breast cancer models for studying mechanisms of resistance to endocrine therapy.

The development of endocrine resistance is a common reason for the failure of endocrine therapies in hormone receptor-positive breast cancer. This review provides an overview of the different types of in vitro models that have been developed as tools for studying endocrine resistance. In vitro models include cell lines that have been rendered endocrine-resistant by ex vivo treatment; cell lines with de novo resistance mechanisms, including genetic alterations; three-dimensional (3D) spheroid, co-culture, and mammosphere techniques; and patient-derived organoid models. In each case, the key discoveries, different analysis strategies that are suitable, and strengths and weaknesses are discussed. Certain recently developed methodologies that can be used to further characterize the biological changes involved in endocrine resistance are then emphasized, along with a commentary on the types of research outcomes that using these techniques can support. Finally, a discussion anticipates how these recent developments will shape future trends in the field. We hope this overview will serve as a useful resource for investigators that are interested in understanding and testing hypotheses related to mechanisms of endocrine therapy resistance.

SARS-CoV-2 Omicron: Light at the End of the Long Pandemic Tunnel or Another False Dawn for Immunodeficient Patients?

COVID-19 has had a disastrous impact on the world. Apart from at least 6 million deaths, countless COVID-19 survivors are suffering long-term physical and psychiatric morbidity. Hundreds of millions have been plunged into poverty caused by economic misery, particularly in developing nations. Early in the pandemic, it became apparent certain groups of individuals such as the elderly and those with comorbidities were more likely to suffer severe disease. In addition, patients with some forms of immunodeficiency, including those with T-cell and innate immune defects, were at risk of poor outcomes. Patients with immunodeficiencies are also disadvantaged as they may not respond optimally to COVID-19 vaccines and often have pre-existing lung damage. SARS-CoV-2 Omicron (B.1.529) and its subvariants (BA.1, BA.2, etc) have emerged recently and are dominating COVID-19 infections globally. Omicron is associated with a reduced risk of hospitalization and appears to have a lower case fatality rate compared with previous SARS-CoV-2 variants. Omicron has offered hope the pandemic may finally be coming to an end, particularly for vaccinated, healthy individuals. The situation is less clear for individuals with vulnerabilities, particularly immunodeficient patients. This perspective offers insight into potential implications of the SARS-CoV-2 Omicron variant for patients with immunodeficiencies.

Severe COVID-19 is a T cell immune dysregulatory disorder triggered by SARS-CoV-2.

INTRODUCTION: COVID-19 has had a calamitous impact on the global community. Apart from at least 6 M deaths, hundreds of millions have been infected and a much greater number have been plunged into poverty. Vaccines have been effective but financial and logistical challenges have hampered their rapid global deployment. Vaccine disparities have allowed the emergence of new SARS-CoV-2 variants including delta and omicron, perpetuating the pandemic. AREAS COVERED: The immunological response to SARS-CoV-2 is now better understood. Many of the clinical manifestations of severe disease are a consequence of immune dysregulation triggered by the virus. This may explain the lack of efficacy of antiviral treatments, such as convalescent plasma infusions, given later in the disease. EXPERT OPINION: T cells play a crucial role in both the outcome of COVID-19 as well as the protective response to vaccines. Vaccines do not prevent infection but reduce the risk of a chaotic and destructive cellular immune response to the virus. Severe COVID-19 should be considered a virus-induced secondary immune dysregulatory disorder of cellular immunity, with broad host susceptibility. This perspective of COVID-19 will lead to better diagnostic tests, vaccines, and therapeutic strategies in the future.

The enantioselective total syntheses of (+)-7-oxohinokinin, (+)-7-oxoarcitin, (+)-conicaol B and (-)-isopolygamain.

A flexible approach to C7 keto dibenzyl butyrolactone lignans was developed and the synthesis of several natural products and their related derivatives is described herein. The developed pathway proceeds through enantioenriched ß-substituted butyrolactones, from which facile aldol addition and subsequent oxidation affords the desired benzylic ketone moiety. This methodology was used to complete the first enantioselective total syntheses of three natural products, (+)-7-oxohinokinin, (+)-7-oxoarcitin and (+)-conicaol B, and a further five analogues. The utility of this method was further demonstrated through a 1-2 step modification to access another class of natural product, aryltetralin lignans, allowing the asymmetric total synthesis of (-)-isopolygamain and a polygamain derivative. Anti-proliferative testing determined (-)-isopolygamain was the most active of the compounds prepared, with IC50 values of 2.95 ± 0.61 µM and 4.65 ± 0.68 µM against MDA-MB-231 (triple negative breast cancer) and HCT-116 (colon cancer) cell lines, respectively.