| 35766385 |
Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity |
10.1021/acsinfecdis.2c00008. |
ACS Infect Dis |
Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity
Abstract
- There is a pressing need for host-directed therapeutics that elicit broad-spectrum antiviral activities to potentially address current and future viral pandemics. Apratoxin S4 (Apra S4) is a potent Sec61 inhibitor that prevents cotranslational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to anticancer and antiangiogenic activity both in vitro and in vivo. Since Sec61 has been shown to be an essential host factor for viral proteostasis, we tested Apra S4 in cellular models of viral infection, including SARS-CoV-2, influenza A virus, and flaviviruses (Zika, West Nile, and Dengue virus). Apra S4 inhibited viral replication in a concentration-dependent manner and had high potency particularly against SARS-CoV-2 and influenza A virus, with subnanomolar activity in human cells. Characterization studies focused on SARS-CoV-2 revealed that Apra S4 impacted a post-entry stage of the viral life-cycle. Transmission electron microscopy revealed that Apra S4 blocked formation of stacked double-membrane vesicles, the sites of viral replication. Apra S4 reduced dsRNA formation and prevented viral protein production and trafficking of secretory proteins, especially the spike protein. Given the potent and broad-spectrum activity of Apra S4, further preclinical evaluation of Apra S4 and other Sec61 inhibitors as antivirals is warranted.
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| 35890511 |
The Influence of Plant Stress Hormones and Biotic Elicitors on Cyclotide Production in Cell Suspension Cultures |
10.3390/plants11141876. |
Plants (Basel) |
The Influence of Plant Stress Hormones and Biotic Elicitors on Cyclotide Production in Cell Suspension Cultures
Abstract
- Cyclotides are macrocycle peptides produced by plants from several families, including Violaceae. These compounds have the potential for applications in medicine, bioengineering and crop protection thanks to their multiple biological activities. In most cases, cyclotides are extracted from plant material. Plant cell culture provides a viable and sustainable form of plant biomass production Cyclotides are host defense peptides. The aim of the current study was to test whether different plant stress hormones and biological elicitors have effects on cyclotide production in suspension cultures. Different concentrations of jasmonic acid (JA), salicylic acid (SA), abscisic acid (ABA) and neutralized pathogens were tested. The cyclotide production was assessed using MALDI-MS. Five major peptides produced by cultures were chosen for analysis, of which one was sequenced de novo. The treatments had little influence on the suspension's growth, with the exception of 100 μM SA, which enhanced the biomass increase, and 100 μM ABA, which was toxic. Significant increases in the production of three cyclotides (viul M, cyO13 and cyO3) were observed in suspensions primed with JA (50 μM, 100 μM, 200 μM) after 14 days of culturing. Biotic elicitors had no observable effect on cyclotide production. The current study indicates that some cyclotides in are triggered in response to JA. The stress plant hormones can be used to enhance plant cell culture-based production systems.
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| 36038932 |
A novel antibiotic combination of linezolid and polymyxin B octapeptide PBOP against clinical Pseudomonas aeruginosa strains |
10.1186/s12941-022-00531-5. |
Ann Clin Microbiol Antimicrob |
A novel antibiotic combination of linezolid and polymyxin B octapeptide PBOP against clinical Pseudomonas aeruginosa strains
Abstract
- Antibiotic-resistant Gram-negative bacteria are becoming a major public health threat such as the important opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study investigated enhancement of the linezolid spectrum, which is normally used to treat Gram-positive bacteria, at inhibiting P. aeruginosa growth.
The checkerboard test or time-kill assay were carried out to determine the antibacterial effects of linezolid in cooperation with polymyxin B octapeptide PBOP (LP) against P. aeruginosa based on in vitro model. The protective effect of LP against P. aeruginosa infection was assessed based on a Caenorhabditis elegans (C. elegans) model.
The synergistic activity and antibacterial effects were significantly increased against P. aeruginosa by LP treatment, while linezolid and PBOP as monotherapies exhibited no remarkably bactericidal activity against the clinical strains. Additionally, LP treatment modified biofilm production, morphology, swimming motility of P. aeruginosa, and protected C. elegans from P. aeruginosa infection.
This research demonstrates that LP combination has significant synergistic activity against P. aeruginosa, and PBOP is potential to be an activity enhancer. Notably, this strategy improved the antibacterial activity spectrum of linezolid and other anti-Gram-positive agents and represents an effective choice to surmount the antibiotic resistance of bacteria in the long term.
|
| 36044031 |
Cytotoxic Cyclotides from , a South American Plant Species |
10.1021/acs.jnatprod.1c01129. |
J Nat Prod |
Cytotoxic Cyclotides from , a South American Plant Species
Abstract
- Cyclotides are mini-proteins with potent bioactivities and outstanding potential for agricultural and pharmaceutical applications. More than 450 different plant cyclotides have been isolated from six angiosperm families. In Brazil, studies involving this class of natural products are still scarce, despite its rich floristic diversity. Herein were investigated the cyclotides from roots, a South American medicinal plant from the family Violaceae. Fourteen putative cyclotides were annotated by LC-MS. Among these, three new bracelet cyclotides, anpy A-C, and the known cycloviolacins O4 (cyO4) and O17 (cyO17) were sequenced through a combination of chemical and enzymatic reactions followed by MALDI-MS/MS analysis. Their cytotoxic activity was evaluated by a cytotoxicity assay against three human cancer cell lines (colorectal carcinoma cells: HCT 116 and HCT 116 and breast adenocarcinoma, MCF 7). For all assays, the IC values of isolated compounds ranged between 0.8 and 7.3 μM. CyO17 was the most potent cyclotide for the colorectal cancer cell lines (IC, 0.8 and 1.2 μM). Furthermore, the hemolytic activity of anpy A and B, cyO4, and cyO17 was assessed, and the cycloviolacins were the least hemolytic (HD > 156 μM). This work sheds light on the cytotoxic effects of the anpy cyclotides against cancer cells. Moreover, this study expands the number of cyclotides obtained to date from Brazilian plant biodiversity and adds one more genus containing these molecules to the list of the Violaceae family.
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| 36193595 |
Biochemical characterization of a cyanobactin arginine- -prenylase from the autumnalamide biosynthetic pathway |
10.1039/d2cc01799g. |
Chem Commun (Camb) |
Biochemical characterization of a cyanobactin arginine- -prenylase from the autumnalamide biosynthetic pathway
Abstract
- Cyanobactins are linear and cyclic post-translationally modified peptides. Here we show that the prenyl-D-Arg-containing autumnalamide A is a member of the cyanobactin family. Biochemical assays demonstrate that the AutF prenyltransferase targets the guanidinium moiety in arginine and homoarginine and is a useful tool for biotechnological applications.
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| 36207817 |
SIRT1/Notch1 signal axis involves in the promoting effect of Segetalin B on bone formation |
10.1002/ddr.22001. |
Drug Dev Res |
SIRT1/Notch1 signal axis involves in the promoting effect of Segetalin B on bone formation
Abstract
- Phytoestrogens are a class of potential natural medicines for treating postmenopausal osteoporosis (PMOP). Segetalin B (SB) is a cyclic peptide compound showing estrogenic activity. This study reports the effect of SB on bone formation among ovariectomized (OVX) rats. The bone marrow mesenchymal stem cells (BMSCs) from OVX rats were cultured in vitro. Alizarin Red staining was utilized to observe the effect of SB on the mineralization of BMSCs. The levels of alkaline phosphatase (ALP), osteocalcin, bone morphogenetic protein (BMP-2), and Sirtuin 1 (SIRT1) activities were detected. The OVX rats were treated with SB in vivo. Micro-CT was utilized for imaging analysis. Urine calcium and phosphorus, and ALP activity in bone marrow were assayed. Western blot analysis and immunofluorescence were incorporated to detect protein expressions in vitro and in vivo. The results showed that SB dose-dependently promoted mineralization of OVX rat-derived BMSCs in vitro increased the level of Osteocalcin, BMP-2, ALP, and SIRT1 activity. Moreover, it upregulated expressions of Runx2, Osterix, and SIRT1, downregulated expressions of Notch intracellular domain (NICD), acetyl-NICD, and hairy and enhancer of split 1 (Hes1). In addition, SB treatment significantly decreased bone loss, inhibited calcium and phosphorus loss, elevated ALP activity, upregulated Runx2, Osterix, and SIRT1, and downregulated NICD and Hes1 in OVX rats in vivo. However, EX527, a SIRT1-selective inhibitor, could reverse the above effects of SB in vitro or in vivo. These results indicate that SB is a potential natural medicine to improve PMOP. Thus, its mechanism of promoting bone formation involves the SIRT1/Notch1 signaling axis.
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| 36286522 |
Antibiotic Acyldepsipeptides Stimulate the Clp-ATPase/ClpP Complex for Accelerated Proteolysis |
10.1128/mbio.01413-22. |
mBio |
Antibiotic Acyldepsipeptides Stimulate the Clp-ATPase/ClpP Complex for Accelerated Proteolysis
Abstract
- Clp proteases consist of a proteolytic, tetradecameric ClpP core and AAA+ Clp-ATPases. Streptomycetes, producers of a plethora of secondary metabolites, encode up to five different ClpP homologs, and the composition of their unusually complex Clp protease machinery has remained unsolved. Here, we report on the composition of the housekeeping Clp protease in , consisting of a heterotetradecameric core built of ClpP1, ClpP2, and the cognate Clp-ATPases ClpX, ClpC1, or ClpC2, all interacting with ClpP2 only. Antibiotic acyldepsipeptides (ADEP) dysregulate the Clp protease for unregulated proteolysis. We observed that ADEP binds ClpP1, but not ClpP2, thereby not only triggering the degradation of nonnative protein substrates but also accelerating Clp-ATPase-dependent proteolysis. The explanation is the concomitant binding of ADEP and Clp-ATPases to opposite sides of the ClpP1P2 barrel, hence revealing a third, so far unknown mechanism of ADEP action, i.e., the accelerated proteolysis of native protein substrates by the Clp protease. Clp proteases are antibiotic and anticancer drug targets. Composed of the proteolytic core ClpP and a regulatory Clp-ATPase, the protease machinery is important for protein homeostasis and regulatory proteolysis. The acyldepsipeptide antibiotic ADEP targets ClpP and has shown promise for treating multiresistant and persistent bacterial infections. The molecular mechanism of ADEP is multilayered. Here, we present a new way how ADEP can deregulate the Clp protease system. Clp-ATPases and ADEP bind to opposite sides of ClpP, accelerating the degradation of natural Clp protease substrates. We also demonstrate the composition of the major Clp protease complex, a heteromeric ClpP1P2 core with the Clp-ATPases ClpX, ClpC1, or ClpC2 exclusively bound to ClpP2, and the killing mechanism of ADEP in .
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| 36442484 |
Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial |
10.1016/S0140-6736(22)02324-8. |
Lancet |
Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial
Abstract
- Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis.
ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, , and is complete.
Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events.
Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development.
Cidara Therapeutics and Mundipharma.
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| 36477022 |
LC-MS/MS identification and structural characterization of isolated cyclotides from precursor sequences of petiole tissue using computational approach |
None |
J Biosci |
LC-MS/MS identification and structural characterization of isolated cyclotides from precursor sequences of petiole tissue using computational approach
Abstract
- , known for its pharmacological properties, produces a plethora of structurally stable peptides called cyclotides. Cyclotides are macrocyclic peptides with a unique topology containing a cyclic cystine knot motif. The objective of the present study was to identify the precursor sequences and respective cyclotide domains from the petiole tissue of . The study is based on the isolation, identification, and characterization of the cyclic peptides using LC-MS/MS followed by database searching and processing. Our study detected 47 precursor sequences encoded for 15 reported cyclotides, 4 putative novel cyclotides, and 3 acyclotides from the petiole tissue. The novel sequences identified were based on the hydrophobic nature, disulfide bonds, conserved cysteine residues, and presence of cyclic peptide backbone. Four putative novel and three acyclotides were also characterized for their sequence and subfamilies. A protein diversity wheel was used to reveal the variation in the amino acid sequence and cysteine residue conservation in the isolated cyclotides. The results provide information about the number of cyclotides and acyclotides from the petiole tissue and their sequence diversity, which may constitute novel tools for future research on this plant species.
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| 36525646 |
Screening for Cyclotides in Sri Lankan Medicinal Plants: Discovery, Characterization, and Bioactivity Screening of Cyclotides from |
10.1021/acs.jnatprod.2c00674. |
J Nat Prod |
Screening for Cyclotides in Sri Lankan Medicinal Plants: Discovery, Characterization, and Bioactivity Screening of Cyclotides from
Abstract
- Cyclotides are an intriguing class of structurally stable circular miniproteins of plant origin with numerous potential pharmaceutical and agricultural applications. To investigate the occurrence of cyclotides in Sri Lankan flora, 50 medicinal plants were screened, leading to the identification of a suite of new cyclotides from of the family Rubiaceae. Cycloviolacin O2-like (cyO2-like) gere 1 and the known cyclotide kalata B7 (kB7) were among the cyclotides characterized at the peptide and/or transcript level together with several putative enzymes, likely involved in cyclotide biosynthesis. Five of the most abundant cyclotides were isolated, sequenced, structurally characterized, and screened in antimicrobial and cytotoxicity assays. All gere cyclotides showed cytotoxicity (IC of 2.0-10.2 μM), but only gere 1 inhibited standard microbial strains at a minimum inhibitory concentration of 4-16 μM. As shown by immunohistochemistry, large quantities of the cyclotides were localized in the epidermis of the leaves and petioles of . Taken together with the cytotoxicity and membrane permeabilizing activities, this implicates gere cyclotides as potential plant defense molecules. The presence of cyO2-like gere 1 in a plant in the Rubiaceae supports the notion that phylogenetically distant plants may have coevolved to express similar cytotoxic cyclotides for a specific functional role, most likely involving host defense.
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| 36628602 |
Diastereoselective synthesis of cyclic tetrapeptide pseudoxylallemycin A illuminates the impact of base during macrolactamization |
10.1039/d2ob02126a. |
Org Biomol Chem |
Diastereoselective synthesis of cyclic tetrapeptide pseudoxylallemycin A illuminates the impact of base during macrolactamization
Abstract
- Therapeutic agents with unique molecular structures and new mechanisms of action are needed to confront the phenomenon of multidrug resistance among bacteria. Pseudoxylallemycins, cyclic tetrapeptide (CTP) natural products, have exhibited modest antibiotic activity, but their synthesis has proven challenging. Inherent ring strain in CTPs decreases the rate of cyclization in lieu of polymerization and racemization pathways, which has resulted in previous syntheses describing mixtures of diastereomers containing predominantly an undesired epimer. We have optimized the cyclization step of pseudoxylallemycin A to favor production of the natural diastereomer; notably, variation of the base, temperature, and solvent with peptide coupling reagent propylphosphonic anhydride (T3P) afforded exquisite selectivity for the natural product in as high as 97 : 3 DR, and our conditions can provide the natural product in up to 32% overall yield through 8 steps. Employing weaker bases than those typically used in peptide coupling reactions led to the greatest improvement in diastereoselectivity, and these studies demonstrated that the identity of the amine base has enormous impact on the rate of C-terminal epimerization when T3P is used, a variable usually considered of lesser consequence when combined with typical amide coupling reagents. Toward fully characterizing pseudoxylallemycin stereoisomers, variable temperature NMR was described as a tool to more clearly analyze CTPs that exhibit multiple conformational states. These synthetic and spectroscopic insights were applied toward synthesizing several natural product analogues, and their antibacterial activity was examined using microdilution assays.
|
| 36651671 |
Rational Optimizations of the Marine-Derived Peptide Sungsanpin as Novel Inhibitors of Cell Invasion |
10.1002/cbdv.202201221. |
Chem Biodivers |
Rational Optimizations of the Marine-Derived Peptide Sungsanpin as Novel Inhibitors of Cell Invasion
Abstract
- Cancer metastasis, including cell invasion, is a major cause of poor clinical outcomes and death in numerous cancer patients. In recent years, many efforts have been made to develop potent therapeutic molecules from naturally derived peptides. Sungsanpin is a naturally derived lasso peptide that inhibits A549 cell invasion. We aimed to evaluate the potential of sungsanpin derivatives as candidates for anti-invasion drugs. We synthesized an analog of sungsanpin (Sun A) using a solid-phase peptide synthesis strategy (SPPS) and further modified its structure to improve its anti-invasion activity. All peptides were tested for their proliferative inhibition and anti-invasion activities in the A549 cell lines. Octapeptide S3 and cyclooctapeptide S4 upregulated the expression of TIMP-1 and TIMP-2 mRNA effectively and thus improved the inhibitory effect on the invasion of A549 cells. The two peptides can inhibit the invasion of A549 cells by up to 60 %, suggesting that they have potential as lead molecules for the development of peptide inhibitors.
|
| 36669196 |
Ecological Niche-Inspired Genome Mining Leads to the Discovery of Crop-Protecting Nonribosomal Lipopeptides Featuring a Transient Amino Acid Building Block |
10.1021/jacs.2c11107. |
J Am Chem Soc |
Ecological Niche-Inspired Genome Mining Leads to the Discovery of Crop-Protecting Nonribosomal Lipopeptides Featuring a Transient Amino Acid Building Block
Abstract
- Investigating the ecological context of microbial predator-prey interactions enables the identification of microorganisms, which produce multiple secondary metabolites to evade predation or to kill the predator. In addition, genome mining combined with molecular biology methods can be used to identify further biosynthetic gene clusters that yield new antimicrobials to fight the antimicrobial crisis. In contrast, classical screening-based approaches have limitations since they do not aim to unlock the entire biosynthetic potential of a given organism. Here, we describe the genomics-based identification of keanumycins A-C. These nonribosomal peptides enable bacteria of the genus to evade amoebal predation. While being amoebicidal at a nanomolar level, these compounds also exhibit a strong antimycotic activity in particular against the devastating plant pathogen and they drastically inhibit the infection of leaves using only supernatants of cultures. The structures of the keanumycins were fully elucidated through a combination of nuclear magnetic resonance, tandem mass spectrometry, and degradation experiments revealing an unprecedented terminal imine motif in keanumycin C extending the family of nonribosomal amino acids by a highly reactive building block. In addition, chemical synthesis unveiled the absolute configuration of the unusual dihydroxylated fatty acid of keanumycin A, which has not yet been reported for this lipodepsipeptide class. Finally, a detailed genome-wide microarray analysis of exposed to keanumycin A shed light on the mode-of-action of this potential natural product lead, which will aid the development of new pharmaceutical and agrochemical antifungals.
|
| 36855391 |
Novel Therapeutic Approaches to Invasive Candidiasis: Considerations for the Clinician |
10.2147/IDR.S375625. |
Infect Drug Resist |
Novel Therapeutic Approaches to Invasive Candidiasis: Considerations for the Clinician
Abstract
- Invasive candidiasis (IC), due to the yeast pathogen , is still a major cause of in-hospital morbidity and mortality. The limited number of antifungal drug classes and the emergence of multi-resistant species, such as and some isolates, is concerning. However, recent advances in antifungal drug development provide promising perspectives for the therapeutic approach of IC. Notably, three novel antifungal agents, currently in Phase II/III clinical trials, are expected to have an important place for the treatment of IC in the future. Rezafungin is a novel echinocandin with prolonged half-life. Ibrexafungerp and fosmanogepix are two first-in-class antifungal drugs with broad spectrum activity against spp., including and echinocandin-resistant species. These novel antifungal agents also represent interesting alternative options because of their acceptable oral bioavailability (ibrexafungerp and fosmanogepix) or their large interdose interval (once weekly intravenous administration for rezafungin) for prolonged and/or outpatient treatment of complicated IC. This review discusses the potential place of these novel antifungal drugs for the treatment of IC considering their pharmacologic properties and their preclinical and clinical data.
|
| 36889610 |
Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616 |
10.1016/j.jacc.2023.02.018 |
J Am Coll Cardiol. |
Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616
Abstract
- Background: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia.Objectives: This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia.Methods: This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period.Results: Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group.Conclusions: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126). Keywords: PCSK9; atherosclerotic cardiovascular disease; lipid-lowering medications; low-density lipoprotein cholesterol; macrocyclic peptides.
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