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Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 µg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.
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Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Animais , Humanos , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Relação Dose-Resposta a Droga , Imunoconjugados/química , Imunoconjugados/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-Atividade , Rifamicinas/química , Rifamicinas/farmacologiaRESUMO
The epidermal growth factor receptor (EGFR) has received significant attention as a potential target for glioblastoma (GBM) therapeutics in the past two decades. However, although cetuximab, an antibody that specifically targets EGFR, exhibits a high affinity for EGFR, it has not yet been applied in the treatment of GBM. Antibody-drug conjugates (ADCs) utilize tumor-targeting antibodies for the selective delivery of cytotoxic drugs, resulting in improved efficacy compared to conventional chemotherapy drugs. However, the effectiveness of cetuximab as a targeted antibody for ADCs in the treatment of GBM remains uncertain. In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared to temozolomide (TMZ). In summary, this study presents a novel ADC for GBM therapy that utilizes cetuximab as the tumor-targeting antibody, resulting in effective delivery of the cytotoxic drug payload.
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Antineoplásicos , Glioblastoma , Imunoconjugados , Humanos , Animais , Camundongos , Cetuximab/farmacologia , Preparações Farmacêuticas , Glioblastoma/metabolismo , Anticorpos , Antineoplásicos/uso terapêutico , Receptores ErbB , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Introduction: Randomized, controlled trials of molnupiravir in real-world use during the Omicron wave are scarce. The frequency of hospitalization and death is low, so further research is needed to confirm the virological efficacy of molnupiravir. Methods: A single-center, randomized, controlled clinical trial was conducted, and 111 hospitalized coronavirus disease 2019 (COVID-19) patients were randomly assigned at a ratio of 1:1. Fifty-three patients in the molnupiravir group were administered 800 mg of molnupiravir twice daily for 5 days in addition to the standard therapy, and 58 patients in the control group only received the standard therapy in accordance with local guidelines. The antiviral effect and adverse events were evaluated during the follow-up. Results: The median viral clearance time in the molnupiravir group was significantly shorter than that in the control group (p = 0.003). Furthermore, patients who started molnupiravir therapy within 3 days had significantly shorter viral clearance time than the controls (p = 0.003). In the vaccinated subgroup, molnupiravir therapy was also associated with a shorter viral clearance time (p = 0.003). A total of three adverse events, which were minor, were reported in the molnupiravir group. One of the patients had mild liver function abnormalities, and all of them were resolved without intervention. However, the remission time was similar between the two tested groups. Conclusion: Molnupiravir exhibited good viral replication inhibitor efficacy in patients with Omicron variant vaccine breakthrough COVID-19 infection. Clinical Trial Registration: [https://www.chictr.org.cn/], identifier [ChiCTR2200059796].
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Introduction: The collection and process of human brain activity signals play an essential role in developing brain-computer interface (BCI) systems. A portable electroencephalogram (EEG) device has become an important tool for monitoring brain activity and diagnosing mental diseases. However, the miniaturization, portability, and scalability of EEG recorder are the current bottleneck in the research and application of BCI. Methods: For scalp EEG and other applications, the current study designs a 32-channel EEG recorder with a sampling rate up to 30 kHz and 16-bit accuracy, which can meet both the demands of scalp and intracranial EEG signal recording. A fully integrated electrophysiology microchip RHS2116 controlled by FPGA is employed to build the EEG recorder, and the design meets the requirements of high sampling rate, high transmission rate and channel extensive. Results: The experimental results show that the developed EEG recorder provides a maximum 30 kHz sampling rate and 58 Mbps wireless transmission rate. The electrophysiological experiments were performed on scalp and intracranial EEG collection. An inflatable helmet with adjustable contact impedance was designed, and the pressurization can improve the SNR by approximately 4 times, the average accuracy of steady-state visual evoked potential (SSVEP) was 93.12%. Animal experiments were also performed on rats, and spike activity was captured successfully. Conclusion: The designed multichannel wireless EEG collection system is simple and comfort, the helmet-EEG recorder can capture the bioelectric signals without noticeable interference, and it has high measurement performance and great potential for practical application in BCI systems.
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Many clinical trials of kinesin spindle protein (KSP) inhibitors have failed due to issues such as high toxicity and a short circulation half-life in vivo. To address the limitations of current KSP inhibitors and thus broad its use in antitumor therapy, this study applied antibody-drug conjugate (ADC) technology to the KSP inhibitor SB-743921, which was coupled with the HER2-specific antibody trastuzumab using a cathepsin B-dependent valine-alanine (Val-Ala, VA) dipeptide-type linker to generate H2-921. Ex vivo and in vivo analyses of H2-921 showed an increased half-life of SB-743921 and prolonged contact time with tumor cells. Furthermore, H2-921 induced apoptosis and incomplete autophagy in HER2-positive cells. In the in vivo analyses, H2-921 had significant tumor-targeting properties, and tumor inhibition by H2-921 was greater than that by traditional KSP inhibitors but similar to that by the positive control drug T-DM1. In conclusion, this study describes a novel application of ADC technology that enhances the antitumor effects of a KSP inhibitor and thus may effectively address the poor clinical efficacy of KSP inhibitors.
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Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Cinesinas/metabolismo , Trastuzumab , Neoplasias/tratamento farmacológico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route-dependent pulmonary biodistribution of TET associated with its efficacy.
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INTRODUCTION: The efficacy of molnupiravir (MLN) on Omicron sublineages is limited. We investigated the effectiveness of MLN in older adults diagnosed with Omicron BA.2. METHODS: Data of elderly COVID-19 patients (over 60 years) admitted to Chinghai Hospital (Shanghai, China) from 26 March to 31 May 2022 were reviewed. Study outcomes were a composite of undetectable viral load (VL) and disease progression [all-cause mortality, initiation of oxygen supply through high-flow device or invasive mechanical ventilation (IMV), or intensive care unit (ICU) admission] and their individual outcomes. RESULTS: A total of 42 elderly patients were enrolled: 26 of them received MLN, 17 (40.5%) were males, the median age was 84 years, and 12 were fully vaccinated (31.0%). Among these elderly COVID-19 patients, five (11.90%) experienced obvious dyspnea or were transferred to ICU [three MLN users (11.5%) versus two non-MLN users (12.5%)]. Compared with no MLN use, MLN use was associated with rapid undetectable VL. At day 10, MLN users achieved significantly greater undetectable VL than non-MLN users. Adjusted analysis showed that elderly patients who received MLN were 7.584 times more likely to achieve undetectable VL at day 10 than non-MLN users. Overall, elderly patients experienced a median hospital stay of 13 days. Compared with patients receiving standard care (SC), the median hospital stay of MLN users was reduced by 2.5 days. CONCLUSION: Early initiation of MLN in elderly COVID-19 was associated with fast undetectable VL and short hospital stay.
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Enterovirus D68 (EV-D68) is a nonpolio enterovirus that is mainly transmitted through respiratory routes and poses a potential threat for large-scale spread. EV-D68 infections mostly cause moderate to severe respiratory diseases in children and potentially induce neurological diseases. However, there are no specific antiviral drugs or vaccines against EV-D68. Herein, through virtual screening and rational design, a series of novel quinoline analogues as anti-EV-D68 agents targeting VP1 were identified. Particularly, 19 exhibited potent antiviral activity with an EC50 value ranging from 0.05 to 0.10 µM against various EV-D68 strains and showed inhibition of viral replication verified by Western blot, immunofluorescence, and plaque formation assay. Mechanistic studies indicated that the anti-EV-D68 agents work mainly by interacting with VP1. The acceptable bioavailability of 23.9% in rats and significant metabolic stability in human liver microsome (Clint = 10.8 mL/min/kg, t1/2 = 148 min) indicated that compound 19 with a novel scaffold was worth further investigation.
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Enterovirus Humano D , Infecções por Enterovirus , Enterovirus , Quinolinas , Infecções Respiratórias , Criança , Humanos , Ratos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Infecções por Enterovirus/tratamento farmacológico , Quinolinas/farmacologia , Quinolinas/uso terapêuticoRESUMO
Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/ß-catenin, TGF-ß, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Selênio , Selênio , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Detecção Precoce de Câncer , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Simulação de Acoplamento Molecular , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Selênio/metabolismo , Selênio/farmacologia , Compostos de Selênio/metabolismo , Compostos de Selênio/farmacologia , Sorafenibe/metabolismo , Sorafenibe/farmacologiaRESUMO
Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.
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Orelha Interna , Perda Auditiva , Sistemas de Liberação de Medicamentos , Orelha Interna/irrigação sanguínea , Orelha Interna/metabolismo , Perda Auditiva/metabolismo , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Preparações Farmacêuticas/metabolismoRESUMO
Maleimides are typically applicable for coupling with reactive thiol moieties of antibodies in antibody-drug conjugates (ADCs) via the thiol-Michael click chemistry. Even so, the thiosuccinimide group produced in ADCs is unstable under physiological conditions, which is a unresolved issue in the ADC industry that can cause serious off-target toxicity. Committed to solving the stability defects of traditional thiosuccinimide-containing ADCs, we explored a series of linkers based on the ring-opening hydrolysates of thiosuccinimide. Meanwhile, a type of linkers based on maleamic methyl ester were used to conjugate the popular monomethyl auristatin E to an anti-HER2 antibody to generate the target ADCs, which enhances the stability and do not need to change the structure of the ideal stable metabolite of traditional ADCs. In vivo studies demonstrate that our preferred ADC mil40-12b not only has better efficacy than traditional ADCs but also exhibits better safety parameters in mice. For example, complete tumor regression can still be achieved even when the dose is halved (2.5 mg/kg), and the maximum tolerable dose is increased by 40 mg/kg. This strategy is expected to provide an applicable tool for the construction of thiol-linked ADCs with improved therapeutic index.
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Antineoplásicos , Imunoconjugados , Animais , Antineoplásicos/química , Imunoconjugados/química , Maleimidas/química , Camundongos , Compostos de Sulfidrila/química , Índice TerapêuticoRESUMO
Camptothecins, traditional chemotherapy drugs, have been clinically used in antibody-drug conjugates (ADCs), which refreshes the recognition that ADCs preferably incorporate highly potent payloads. However, SN-38, active metabolite of irinotecan from camptothecins, tended to be incorporated into ADCs with an unstable acid sensitive bond, not with the widely used Cathepsin B (CTSB) sensitive bond, which may pose the risk of off-target. Herein, we reported a novel strategy to construct highly releasable and structurally stable SN-38-conjugates, in which CTSB linkers directly connected to the 10-OH group through ether bond, not to the common 20-OH group of lactones of SN-38. In this paper, rapid release of SN-38 was skillfully demonstrated by utilizing the fluorescence properties of SN-38. The SN-38-ether-ADC displayed highly stable serum stability with the half-life over 10 days. Moreover, the drug-antibody-ratio (DAR) of ADC could be elevated to 7.1 through the introduction of polyethylene glycol (PEG) moieties without aggregation. The optimized ADC exhibited potent in vitro activities up to 5.5 nM, comparable to SN-38. Moreover, this ADC group significantly delayed tumor growth in vivo. In conclusion, the novel strategy has the potential to promote the development of SN38-ADCs and enrich the conjugation approaches for hydroxyl-bearing payloads.
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Imunoconjugados/administração & dosagem , Imunoconjugados/farmacologia , Irinotecano/administração & dosagem , Irinotecano/farmacologia , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Imunoconjugados/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Aleatória , Tecnologia Farmacêutica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of phosphoamidate derivatives of nucleoside 2'-acetylene-7-deaza-adenosine (NITD008) were synthesized and evaluated for their in vitro antiviral activities against the enteroviruses EV71 and EV-D68. The phosphoamidate (15f) containing a hexyl ester of l-alanine exhibited the most promising activity against EV71 (IC50 = 0.13 ± 0.08 µM) and was 4-times more potent than NITD008. Meanwhile, the derivative containing a cyclohexyl ester of l-alanine (15l) exhibited the most potent activity with high selectivity index against both EV71 (IC50 = 0.19 ± 0.27 µM, SI = 117.00) and EV-D68 (IC50 = 0.17 ± 0.16 µM, SI = 130.76), which were both higher than that of NITD008. The results indicated that the phosphoamidate 15l was the most promising candidate for further development as antiviral agents for the treatment of both EV71 and EV-D68 infection.
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Adenosina/análogos & derivados , Antivirais/farmacologia , Desenho de Fármacos , Infecções por Enterovirus/tratamento farmacológico , Enterovirus/efeitos dos fármacos , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Infecções por Enterovirus/virologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. Developing novel theranostic ADCs with therapeutic utility and imaging capability is an attractive and challenging subject that promises advances in the field of personalized medicine. In this work, we propose a bifunctional molecule-based strategy for the development of theranostic ADCs. Methods: We developed a theranostic ADC consisting of the anti-Her2 antibody Mil40, monomethyl auristatin E (MMAE) as the active payload, and a 7-amino-3-hydroxyethyl-coumarin (7-AHC)-based dipeptide linker, which functions as a novel bifunctional fluorescence probe that allows self-elimination cleavage in the presence of cathepsin B for payload release and fluorophore activation. The on-off fluorescence properties and the antitumor effect in vitro and in vivo were investigated. Results: A 48-fold fluorescence enhancement was observed within 1 h when the 7-AHC-based linker was exposed to cathepsin B. Cleavage upon exposure to cathepsin B allows MMAE and fluorophore intracellular release and the monitoring of MMAE distribution using confocal microscopy. Additionally, the newly developed ADC retains the advantages of traditional p-aminobenzyloxycarbonyl-containing ADCs, such as good stability (t1/2 > 7 days) and high activity in vitro (IC50 = 0.09-3.74 nM). Importantly, the theranostic ADC exhibited the equivalent antitumor efficacy to the marketed ADC T-DM1 in the classic breast cancer model. Conclusion: We suggest that the present strategy can be universally applied in all p-aminobenzyloxycarbonyl-containing ADCs. Overall, theranostic ADCs may play a role in developing new theranostic systems and promoting personalized medicine research.
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Anticorpos Monoclonais/química , Antineoplásicos/química , Imunoconjugados/química , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Catepsina B/química , Catepsina B/farmacologia , Linhagem Celular Tumoral , Humanos , Imunoconjugados/farmacologia , Células MCF-7 , Camundongos , Camundongos Nus , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Medicina de Precisão/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linkerâantibody attachment and linkerâpayload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.
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Clinically diagnosing low-grade gliomas and microscopic metastatic tumors in the spinal cord using magnetic resonance imaging (MRI) is challenging, as the blood-brain barrier (BBB) almost completely excludes the MRI contrast agent gadopentetate dimeglumine, GdDTPA (Magnevist), from the brain. The development of a more efficient, safe, and broad-spectrum glioma diagnosis and treatment would therefore have a great clinical value. Based on the high expression levels of both transferrin receptor 1 (TfR1) and low-density lipoprotein receptor-related protein 1 (LRP1) in BBB-related cells and glioma cells, we designed a novel protein nanoparticle, ferritin-HREV107-Angiopep-2 (Fn-Rev-Ang). We found that Fn-Rev-Ang rapidly crossed the BBB in mice and had drug-loading properties. Moreover, the brain MRI signal intensity ratio associated with Fn-Rev-Ang-GdDTPA was higher than that associated with Fn-GdDTPA alone. Importantly, gliomas with diameters below 1 mm and microscopic metastatic tumors in the spinal cord were successfully detected in mice by MRI with Fn-Rev-Ang-GdDTPA, which is not possible using the current clinical MRI technology. In addition, Fn-Rev-Ang-loaded doxorubicin had a strong inhibitory effect on mouse brain gliomas and their metastasis, which significantly prolonged the animal survival time. Thus, our newly constructed Fn-Rev-Ang nanodelivery carrier may help expand the use of MRI to the early diagnosis and treatment of microscopic tumors, thereby offering a possible basis for improving the survival rate of patients with gliomas and microscopic spinal metastatic tumors.
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Bedaquiline (TMC207), a typical diarylquinoline anti-tuberculosis drug, has been approved by FDA to specifically treat MDR-TB. Herein we describe design, synthesis, and in vitro biological evaluation against Mycobacterium tuberculosis of a series of triaryldimethylaminobutan-2-ol derivatives obtaining from the structural modification of TMC207. Compounds 23, 25, 28, 32, 39 and 43 provided superior anti-mycobacterial activity than positive control PC01 which shows the same configuration and contains TMC207. Compounds 16, 20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive control PC01. Most importantly, the series of compounds showed excellent activity against XDR-Mtb. The result of acute toxicity suggested that this class of triaryldimethylaminobutan-2-ol derivatives should be graded as low. Further SAR analysis indicates that a large steric bulk of triaryl and 7-Br, 3-OCH3 on 1-naphthyl are critical.
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Antituberculosos/uso terapêutico , Diarilquinolinas/síntese química , Diarilquinolinas/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Desenho de Fármacos , HumanosRESUMO
SARS-CoV-2 has been widely spread around the world and COVID-19 was declared a global pandemic by the WHO. Limited clinically effective antiviral drugs are available now. The development of anti-SARS-CoV-2 drugs has become an urgent work worldwide. At present, potential therapeutic targets and drugs for SARS-CoV-2 are continuously reported, and many repositioning drugs are undergoing extensive clinical research, including remdesivir and chloroquine. On the other hand, structures of many important viral target proteins and host target proteins, including that of RdRp and Mpro were constantly reported, which greatly promoted structure-based drug design. This paper summarizes the current research progress and challenges in the development of anti-SARS-CoV-2 drugs, and proposes novel short-term and long-term drug research strategies.
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Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Antivirais/uso terapêutico , Betacoronavirus/química , Betacoronavirus/efeitos dos fármacos , COVID-19 , Ensaios Clínicos como Assunto , Humanos , Pandemias , SARS-CoV-2 , Proteínas Virais/química , Proteínas Virais/efeitos dos fármacosRESUMO
Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced "bystander effect" inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10-11 M), but also shows improved safety with lower bystander toxicity (IC50: 10-9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.