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For accurate and reliable analysis of microplastics (MPs) in wastewater (WW), it is imperative to comprehend the significance of pre-treating WW before analysis. The suspended solids (SS) in the matrix tend to adhere to the MPs during filtration, which interferes with the detection of the MPs. In this regard, the present study aims to develop and optimize a pretreatment method to improve the extraction efficiency of MPs from WW by reducing the SS. A combination of the Fenton reaction and ultrasonication, ferro-sonication (Fe-UlS), was proposed to digest and eliminate the SS from WW. This hybrid pretreatment, Fe-UlS, was optimized for ultrasonication amplitude, treatment time, and hydrogen peroxide dose using response surface methodology (RSM) with a Box-Behnken design, achieving a desirability of 0.984. The optimum conditions for the Fe-UlS, such as the (1:1) Fenton reagent ratio (0.05 M FeSO4: 30 % H2O2), ultrasonication amplitude (31 %), and total process time (30 min) were found to be statistically significant (p < 0.05). The developed method was then employed for the extraction of spiked polyethylene (PE), polypropylene (PP) and polyethylene terephthalate (PET) MPs in real WW and found efficient in removing 83 % of the TSS present in the primary influent were in 30 min at a temperature of 45 °C. Also, the method did not affect the physio-chemical characteristics of the MPs; however, the thermal analysis of PE and PP MPs showed a statistically significant decrease in the melting temperature, as proven by paired t-test analysis. Further, a non-targeted liquid chromatography-mass spectrometry (LC-MS) analysis proved that Fe-UlS is a stable process, as it did not cause any leaching of MPs under the optimum pretreatment conditions. Finally, Laser Direct-Infrared Imaging (LD-IR) analysis was conducted to validate the developed Fe-UlS pretreatment approach for MP analysis in real WW. About 3434 MPs were detected in 100 mL of WW primary influent, within the size range of 9 to 500 µm. This hybrid pretreatment approach not only streamlines WW sample processing but also reduces the required concentration of Fenton reagent and processing time, yielding accurate and reliable results for monitoring MPs in WW.
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Rhodosporidium toruloides has emerged as an excellent option for microbial lipid production due to its ability to accumulate up to 70â¯% of lipids per cell dry weight, consume multiple substrates such as glucose and xylose, and tolerate toxic compounds. Despite the potential of Rhodosporidium toruloides for high lipid yields, achieving these remains is a significant hurdle. A comprehensive review is essential to thoroughly evaluate the advancements in processes and technologies to enhance lipid production in R. toruloides. The review covers various strategies for enhancing lipid production like co-culture, adaptive evolution, carbon flux analysis, as well as different modes of fermentation. This review will help researchers to better understand the recent developments in technologies for sustainable and scalable lipid production from R. toruloides and simultaneously emphasize the need for developing an efficient and sustainable bioprocess.
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Fermentação , Metabolismo dos Lipídeos , Lipídeos , Rhodotorula , Lipídeos/biossíntese , Rhodotorula/metabolismo , Técnicas de Cocultura , Glucose/metabolismo , Xilose/metabolismoRESUMO
There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.
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Antibacterianos , Desenho de Fármacos , Peptídeos Cíclicos , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Testes de Sensibilidade Microbiana , Depsipeptídeos/farmacologia , Depsipeptídeos/química , Lipoproteínas/química , Lipoproteínas/metabolismo , Lipoproteínas/farmacologia , Lipoproteínas/antagonistas & inibidores , Proteínas de Bactérias , Peptídeos , Ácido Aspártico EndopeptidasesRESUMO
Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered macrocycles composed of alpha, beta, gamma, and 17 other amino acid backbone chemistries, which we used to predict 14.9 million closed cycles composed of >42,000 monomer combinations. We chemically synthesized 18 macrocycles predicted to adopt single low-energy states and determined their x-ray or nuclear magnetic resonance structures; 15 of these were very close to the design models. We illustrate the therapeutic potential of these macrocycle designs by developing selective inhibitors of three protein targets of current interest. By opening up a vast space of readily synthesizable drug-like macrocycles, our results should considerably enhance structure-based drug design.
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Amidas , Aminoácidos , Produtos Biológicos , Desenho de Fármacos , Peptídeos Cíclicos , Amidas/química , Aminoácidos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologiaRESUMO
In the realm of high-throughput screening (HTS), macrocyclic peptide libraries traditionally necessitate decoding tags, essential for both library synthesis and identifying hit peptide sequences post-screening. Our innovation introduces a tag-free technology platform for synthesizing cyclic peptide libraries in solution and facilitates screening against biological targets to identify peptide binders through unconventional intramolecular CyClick and DeClick chemistries (CCDC) discovered through our research. This combination allows for the synthesis of diverse cyclic peptide libraries, the incorporation of various amino acids, and facile linearization and decoding of cyclic peptide binder sequences. Our sensitivity-enhancing derivatization method, utilized in tandem with nano LC-MS/MS, enables the sequencing of peptides even at exceedingly low picomolar concentrations. Employing our technology platform, we have successfully unearthed novel cyclic peptide binders against a monoclonal antibody and the first cyclic peptide binder of HIV capsid protein responsible for viral infections as validated by microscale thermal shift assays (TSA), biolayer interferometry (BLI) and functional assays.
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Biblioteca de Peptídeos , Peptídeos Cíclicos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Ensaios de Triagem em Larga Escala , Espectrometria de Massas em TandemRESUMO
Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-ß-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-ß-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-ß-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.
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Analgésicos Opioides , Receptores Opioides kappa , Masculino , Camundongos , Animais , Receptores Opioides kappa/metabolismo , Ligantes , Analgésicos Opioides/química , Receptores Opioides mu/metabolismo , Peptídeos Cíclicos/químicaRESUMO
Background: Positive fusional vergence (PFV) is vital in maintaining fusion in critical and continuous near tasks such as reading or performing digital screen tasks. This study investigated how PFV changed under various lighting conditions. Methods: This cross-sectional study recruited 34 participants aged between 21 and 25 years, with best corrected visual acuity (BCVA) 0.0 logMAR and insignificant refractive error. Three different illuminations-low illumination (50 lux), medium lighting (100 lux), and high illumination (150 lux)-were used to examine the ocular parameters PFV (blur, break, and recovery points), contrast sensitivity and pupil diameter. Results: Pupil diameter changed significantly in different room illuminations (p = 0.00). There was no significant difference in contrast sensitivity across the three levels of room illumination (p = 0.368). Mean PFV (SD) (blur) was 14.5 (2.5) in 50 lux, 10.2 (2.2) in 100 lux, and 8.2 (2.1) in 150 lux. Under 50, 100 and 150 lux, respectively, the mean PFV (SD) (break) values were 16.7 (2.4), 13.4 (1.8), and 10.8 (2.2), and the mean PFV (SD) (recovery) values were 13.3 (2.1), 10.7 (2.1), and 7.5 (2.7). With increased illumination levels, PFV blur, break, and recovery values were significantly lower (p < 0.001). Conclusions: PFV values were significantly higher in lower illumination. Clinicians should be aware that room illumination affected the PFV values measured.
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Membrane-traversing peptides offer opportunities for targeting intracellular proteins and oral delivery. Despite progress in understanding the mechanisms underlying membrane traversal in natural cell-permeable peptides, there are still several challenges to designing membrane-traversing peptides with diverse shapes and sizes. Conformational flexibility appears to be a key determinant of membrane permeability of large macrocycles. We review recent developments in the design and validation of chameleonic cyclic peptides, which can switch between alternative conformations to enable improved permeability through cell membranes, while still maintaining reasonable solubility and exposed polar functional groups for target protein binding. Finally, we discuss the principles, strategies, and practical considerations for rational design, discovery, and validation of permeable chameleonic peptides.
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Lagartos , Peptídeos Cíclicos , Animais , Peptídeos Cíclicos/metabolismo , Lagartos/metabolismo , Peptídeos/química , Conformação Molecular , Permeabilidade da Membrana CelularRESUMO
Deep learning networks offer considerable opportunities for accurate structure prediction and design of biomolecules. While cyclic peptides have gained significant traction as a therapeutic modality, developing deep learning methods for designing such peptides has been slow, mostly due to the small number of available structures for molecules in this size range. Here, we report approaches to modify the AlphaFold network for accurate structure prediction and design of cyclic peptides. Our results show this approach can accurately predict the structures of native cyclic peptides from a single sequence, with 36 out of 49 cases predicted with high confidence (pLDDT > 0.85) matching the native structure with root mean squared deviation (RMSD) less than 1.5 Å. Further extending our approach, we describe computational methods for designing sequences of peptide backbones generated by other backbone sampling methods and for de novo design of new macrocyclic peptides. We extensively sampled the structural diversity of cyclic peptides between 7-13 amino acids, and identified around 10,000 unique design candidates predicted to fold into the designed structures with high confidence. X-ray crystal structures for seven sequences with diverse sizes and structures designed by our approach match very closely with the design models (root mean squared deviation < 1.0 Å), highlighting the atomic level accuracy in our approach. The computational methods and scaffolds developed here provide the basis for custom-designing peptides for targeted therapeutic applications.
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This article is about the accommodation spasm. The primary rule for near vision is ciliary muscle constriction, synchronised convergence of both eyes, and pupil constriction. Any weaknesses in these components could result in an accommodative spasm. Variable retinoscopic reflex, unstable refractive error, and lead of accommodation in near retinoscopy are common causes of spasm. We conducted a thorough literature search in the PubMed and Google Scholar databases for published journals prior to June 2022, with no data limitations. This review contains twenty-eight case reports, six cohort studies, four book references, four review articles, and two comparative studies after applying the inclusion and exclusion criteria. The majority of studies looked at accommodative spasm, near reflex spasm, and pseudomyopia. The most common causes of accommodative spasm are excessive close work, emotional distress, head injury, and strabismus. Despite side effects or an insufficient regimen, cycloplegic drops are effective in diagnosing accommodation spasm. The modified optical fogging technique is also effective and may be an option for treating accommodative spasm symptoms. Bifocals for near work, manifest refraction, base-in prisms, and vision therapy are some of the other management options. As a result, it requires a comprehensive clinical treatment strategy. This review aims to investigate the various aetiology and treatments responsible for accommodative spasm and proposes widely implementing the modified optical fogging method and vision therapy in clinics as comprehensive management to reduce the future upward trend of accommodative spasm.
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Miopia , Erros de Refração , Baixa Visão , Humanos , Acomodação Ocular , Espasmo/diagnóstico , Espasmo/terapia , Espasmo/etiologia , Miopia/etiologia , Midriáticos/uso terapêutico , Baixa Visão/complicaçõesRESUMO
We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10-6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.
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Amidas , Peptídeos , Amidas/química , Hidrogênio , Ligação de Hidrogênio , Lipídeos , Peptídeos/químicaRESUMO
Neuroendocrine tumors (NETs) are rare entities. Most common among them are gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and pulmonary NETs. Most of them are indolent in nature. Colonic NETs are rare among GEP-NETs and mostly present with large size and with metastasis. Emergency presentation with hematochezia is rare in colonic NETs. This case report discusses a rare emergency presentation of colonic NETs and highlights their poor biological nature.
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Diabetic myonecrosis or muscle infarction (DMI), a clinicoradiological entity is an underdiagnosed complication of diabetes mellitus. It refers to spontaneous aseptic necrosis of skeletal muscles commonly of the lower limb without evidence of any large vessel disease. It presents as painful swollen limb without any external insult in patients with long-standing diabetes mellitus with other microvascular complications especially nephropathy. We present four instances of DMI in our patients who had end-stage renal disease with a varied course.
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Diabetes Mellitus Tipo 2 , Falência Renal Crônica , Diabetes Mellitus Tipo 2/complicações , Humanos , Infarto/complicações , Infarto/etiologia , Falência Renal Crônica/complicações , Imageamento por Ressonância Magnética/efeitos adversos , Músculo Esquelético/irrigação sanguíneaRESUMO
OBJECTIVES: To describe, evaluate, and identify the characteristics, prognostic factors, and visual outcomes in patients with intraocular foreign body (IOFB) in a Latin American population. METHODS: A retrospective, observational case-series of patients with a diagnosis of IOFB. Variables analyzed included age, gender, initial and final best correct visual acuity (BCVA), ocular trauma score, intraocular pressure, mechanism of injury, material and number of IOFB, zone of injury, timing of primary repair and IOFB removal, complications, and follow up. RESULTS: Sixty-one patients with IOFB were identified of which 97% were male with a mean age of 37.9 years (SD 2.16). The most common IOFB location was intravitreal (43%). IOFBs were metallic in 78%, vegetal in 3%, and other materials in 11%. Primary repair and secondary IOFB removal were performed at a mean timepoint of 3 days and 5 days, respectively. Systemic and topical antibiotics were administered to all patients. The initial BCVA was 1.62 logMAR and the final was 0.6 logMAR, which was statistically significant (Pearson's chi-squared test, p value 0.01). No cases of endophthalmitis were seen. CONCLUSION: IOFB removal can be delayed when there are no signs of infection or evidence of retinal detachment, without an increased risk of endophthalmitis and a negative impact on visual outcomes. Use of topical and systemic antibiotics appear sufficient to prevent endophthalmitis in these cases.
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Corpos Estranhos no Olho , Ferimentos Oculares Penetrantes , Corpos Estranhos no Olho/diagnóstico , Corpos Estranhos no Olho/cirurgia , Ferimentos Oculares Penetrantes/diagnóstico , Ferimentos Oculares Penetrantes/cirurgia , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Centros de Traumatologia , Resultado do Tratamento , VitrectomiaRESUMO
BACKGROUND: Montefiore Medical Center (MMC) is a large tertiary care center in the Bronx, New York City, with 245 internal medicine residents. Beginning on February 29, 2020, residents became ill with COVID-19-like illness (CLI), which required absence from work. There was initially a shortage of personal protective equipment and delays in SARS-CoV-2 testing, which gradually improved during March and April 2020. OBJECTIVE: We evaluated the relationship between CLI-related work absence rates of internal medicine residents and MMC's COVID-19 hospital census over time. METHODS: Data on resident work absence between February 29 and May 22 were reviewed along with MMC's COVID-19 hospital census data. To determine the effect of patient exposure on resident CLI incidence, we compared the mean incidence of CLI per patient exposure days (PED = daily hospital census × days pre- or post-peak) before and after peak COVID-19 hospital census. RESULTS: Forty-two percent (103 of 245) of internal medicine residents were absent from work, resulting in 875 missed workdays. At the peak of resident work absence, 16% (38 of 245) were out sick. Residents were absent for a median of 7 days (IQR 6-9.5 days). Mean resident CLI incidence per PED (CLI/PED) was 13.9-fold lower post-peak compared to pre-peak (P = .003). CONCLUSIONS: At the beginning of the COVID-19 pandemic in New York City, a large portion of internal medicine residents at this single center became ill. However, the incidence of CLI decreased over time, despite ongoing exposure to patients with COVID-19.
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COVID-19/epidemiologia , Internato e Residência/estatística & dados numéricos , Licença Médica/estatística & dados numéricos , Centros Médicos Acadêmicos , COVID-19/transmissão , Teste para COVID-19 , Humanos , Transmissão de Doença Infecciosa do Paciente para o Profissional , Medicina Interna , Internato e Residência/métodos , Cidade de Nova Iorque/epidemiologia , Exposição Ocupacional , Admissão e Escalonamento de Pessoal , Estudos Retrospectivos , SARS-CoV-2RESUMO
PURPOSE: To determine the results of pars plana vitrectomy for giant retinal tear detachments using transscleral diode laser retinopexy and short-term postoperative tamponade with perfluoro-n-octane (PFnO). METHODS: Twenty consecutive patients with fresh giant retinal tears were enrolled in a single-arm prospective study. One case was withdrawn for technical reasons. The remainder all underwent pars plana vitrectomy, PFnO injection, transscleral diode laser retinopexy to the edge of the giant retinal tear, and short-term postoperative heavy liquid tamponade. None of the cases had scleral buckling or lensectomy. RESULTS: Nineteen cases (18 male and 1 female) with a mean age of 41 years (range 10-69 years) were followed up for a period of 6 months. Postoperative tamponade with PFnO was maintained for a mean of 7.6 days (range 4-21 days), after which it was exchanged for sulfur hexafluoride (SF6), perfluoropropane (C3F8) gas, or balanced salt solution. Final reattachment rate was 100%, with 3 (15.7%) patients requiring additional surgery. Best-corrected visual acuity at final follow-up was 20/40 or better in 11 eyes (58%), between 20/60 and 20/200 in 7 (37%), and 20/400 in 1 (5%). CONCLUSION: In this series of acute giant retinal tears, transscleral diode laser retinopexy together with the use of PFnO for short-term postoperative tamponade achieved excellent anatomical and visual results.
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Tamponamento Interno/métodos , Fluorocarbonos/administração & dosagem , Terapia a Laser/métodos , Lasers Semicondutores/uso terapêutico , Retina/cirurgia , Perfurações Retinianas/cirurgia , Vitrectomia/métodos , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Prospectivos , Retina/patologia , Perfurações Retinianas/diagnóstico , Esclera/cirurgia , Resultado do Tratamento , Acuidade Visual , Adulto JovemRESUMO
INTRODUCTION AND OBJECTIVES: AKI is known to be associated with increased risk of mortality, however limited information is available on how AKI impacts healthcare costs and resource utilization in hospitalized patients with cirrhosis. Previous studies have had variable definitions of AKI, resulting in inconsistent reporting of the true impact of AKI in patients with cirrhosis. METHODS: Data from the Nationwide Inpatient Sample (NIS) which contains data from 44 states and 4378 hospitals, accounting for over 7 million discharges were analyzed. The inclusion data were all discharges in the 2012 NIS dataset with a discharge diagnosis of cirrhosis. RESULTS: A total of 32,605 patients were included in the analysis, incidence of AKI was 12.12% in patients with cirrhosis. Crude mortality was much higher for patients with cirrhosis and AKI (14.9% vs. 1.8%, OR 9.42, p<0.001) than for patients without AKI. In addition, mean LOS was longer (8.5 vs. 4.3 days, p<0.001) and median total hospital charges were higher for patients with AKI ($43,939 vs. $22,270, p<0.001). In multivariate logistic regression, controlling for covariates and mortality risk score, sepsis, ascites and SBP were predictors of AKI. CONCLUSIONS: AKI is relatively common in hospitalized patients with cirrhosis. Presence of AKI results in significantly higher inpatient mortality as well as LOS and resource utilization. Median hospitalization cost was twice as high in AKI patients. Early identification of patients at high risk for AKI should be implemented to reduce mortality and contain costs. Prognosis could be enhanced by utilizing biomarkers which could rapidly detect AKI.
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Injúria Renal Aguda/epidemiologia , Custos de Cuidados de Saúde , Hospitalização/economia , Pacientes Internados/estatística & dados numéricos , Cirrose Hepática/complicações , Injúria Renal Aguda/economia , Injúria Renal Aguda/etiologia , Feminino , Mortalidade Hospitalar/tendências , Humanos , Incidência , Cirrose Hepática/economia , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologiaRESUMO
PURPOSE: To determine the characteristics and outcomes of primary retinal detachment (RD) surgery in aphakic patients. DESIGN: Retrospective case series. PARTICIPANTS: Sixty eyes with primary aphakic RD (ARD) in 51 patients. METHODS: A consecutive series of patients who underwent vitreoretinal surgery for primary rhegmatogenous ARD was analyzed retrospectively between 1997 and 2018 at Moorfields Eye Hospital. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), surgical outcomes, and complications. RESULTS: Mean BCVA improved from 1.31 to 1.08 logarithm of the minimum angle of resolution (logMAR; P = 0.081) over a mean follow-up period of 8.2 years. Macula-off retinal detachments showed significantly improved BCVA from 1.72 to 1.1 logMAR (P = 0.007). Mean age was 38.8 years, and the most common cause of aphakia was congenital cataract surgery (55%). The macula was attached in 45% eyes, and grade C proliferative vitreoretinopathy (PVR) was present in 12%. Operations performed were vitrectomy (88%), combined vitrectomy and scleral buckle (8%), and encirclement (3%). The final anatomic success rate was 88%, and PVR was a significant predictor of redetachment (P = 0.03; odds ratio, 20.7; 95% confidence interval, 2.8-152.2). Raised intraocular pressure was the most common postoperative complication at 30%, with a rate of de novo postoperative glaucoma of 6.7% at final follow-up. CONCLUSIONS: We report high rates of primary and overall anatomic success for surgery in ARD surgery. Grade C PVR was a positive predictor for surgical failure. Final visual outcomes were limited by ocular comorbidity, and we report significant improved visual outcomes for macula-off ARD.
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Afacia/cirurgia , Descolamento Retiniano/cirurgia , Cirurgia Vitreorretiniana/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Acuidade Visual , Adulto JovemRESUMO
Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with l-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of l- and d-amino acids by near-exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods.