AI-DPAPT: a machine learning framework for predicting PROTAC activity.

Proteolysis Targeting Chimeras are part of targeted protein degradation (TPD) techniques, which are significant for pharmacological and therapy development. Small-molecule interaction with the targeted protein is a complicated endeavor and a challenge to predict the proteins accurately. This study used machine learning algorithms and molecular fingerprinting techniques to build an AI-powered PROTAC Activity Prediction Tool that could predict PROTAC activity by examining chemical structures. The chemical structures of a diverse set of PROTAC drugs and their corresponding activities are selected as a dataset for training the tool. The processes used in this study included data preparation, feature extraction, and model training. Further, evaluation was done for the performance of the various classifiers, such as AdaBoost, Support Vector Machine, Random Forest, Gradient Boosting, and Multi-Layer Perceptron. The findings show that the methods selected here depict accurate PROTAC activities. All the models in this study showed an ROC curve better than 0.9, while the random forest on the test set of the AI-DPAPT had an area under the curve score of 0.97, thus showing accurate results. Furthermore, the study revealed significant insights into the molecular features that can influence the functions of the PROTAC. These findings can potentially increase the understanding of the structure-activity correlations involved in the TPD. Overall, the investigation contributes to computational drug development by introducing this platform powered by artificial intelligence that predicts the function of PROTAC. In addition, it sped up the processes of identifying and improving previously unknown medications. The AI-DPAPT platform can be accessed online using a web server at https://ai-protac.streamlit.app/ .

Sinefungin analogs targeting VP39 methyltransferase as potential anti-monkeypox therapeutics: a multi-step computational approach.

The increasing spread of the Monkeypox virus (MPXV) presents a significant public health challenge, emphasising the urgent requirement for effective treatments. Our study focuses on the VP39 Methyltransferase enzyme of MPXV as a critical target for therapy. By utilising virtual screening, we investigated natural compounds with structural similarities to sinefungin, a broad-acting MTase inhibitor. From an initial set of 177 compounds, we identified three promising compounds-CNP0346326, CNP0343532, and CNP008361, whose binding scores were notably close to that of sinefungin. These candidates bonded strongly to the VP39 enzyme, hinting at a notable potential to impede the virus. Our rigorous computational assays, including re-docking, extended molecular dynamics simulations, and energetics analyses, validate the robustness of these interactions. The data paint a promising picture of these natural compounds as front-runners in the ongoing race to develop MPXV therapeutics and set the stage for subsequent empirical trials to refine these discoveries into actionable medical interventions.

Perceptions and Knowledge of Undergraduate Dental Students about Artificial Intelligence in Dental Schools: A Cross-sectional Study.

OBJECTIVE: This study aims to assess the perceptions and knowledge of undergraduate dental students about artificial intelligence (AI) in dental schools through a cross-sectional study. MATERIALS AND METHODS: This was a multicenter, cross-sectional study. Participant recruitment was achieved by sending an online questionnaire to the undergraduate students at the assigned universities. The questionnaire consisted of two parts. The first seven questions record general information about participants and their perceptions of AI. The remaining questions are about the knowledge of participants about the applications of AI. The data were analyzed using SPSS version 26. RESULTS: About 165 undergraduate students from 20 universities related to the dental sciences responded to the questionnaire. And 80.6% of participants found the use of AI in dentistry exciting. I have a basic knowledge of the working principles of AI. About 80.6% of participants believe that applications of AI should be part of undergraduate dental training. And 66.6% of students are aware of the opportunities and threats that AI can create. The results show that 75% of the students indicated that they got their information about AI through social media. Regarding the association of years of studies with AI applications used in periodontics, the knowledge about AI applications in "aggressive periodontics," "compromised teeth," and "success in rate of dental implant" was significantly higher in senior students than junior students (p < 0.05). Concerning applications of AI used in restorative dentistry and prosthodontics, only "computer color matching," "tooth surface losses," and "I do not know" showed statistical significance (p < 0.05) with the year of study of participants. Senior students show significantly better knowledge in "success in retreatment" and "working length determinant." CONCLUSION: Although undergraduates are enthusiastic about AI and aware of its threats and benefits, their knowledge is limited. In addition, undergraduate programs must exert more effort to prepare students for the era of AI. How to cite this article: Aldowah O, Almakrami A, Alghuwaynim Y, et al. Perceptions and Knowledge of Undergraduate Dental Students about Artificial Intelligence in Dental Schools: A Cross-sectional Study. J Contemp Dent Pract 2024;25(2):148-155.

Cardiovascular Mortality in Ovarian Cancer Patients: An Analysis of Patient Characteristics Using the SEER Database.

Background and Objectives: Cardiovascular disease (CVD) is a major contributor to the high mortality rate among individuals with ovarian cancer. Nevertheless, there is limited understanding regarding the specific patient attributes that might impact the risk of CVD in this group. Materials and Methods: A retrospective cohort study was performed using the SEER database to analyze primary ovarian cancer cases from 2000 to 2019. Multivariable logistic regression analysis was employed to identify patient characteristics linked to cardiovascular mortality. Results: The cohort included 41,930 cases of patients who were alive, 54,829 cases of cancer-related deaths, 3003 cases of cardiovascular-related deaths, and 10,238 cases with other causes of death. Poorly differentiated cancer cells and distant metastasis were associated with a higher risk of cardiovascular mortality. Logistic regression analysis identified age, year of diagnosis, race, laterality, and staging as significant risk factors for cardiovascular cause of death. The risk of cardiovascular cause of death was lower in patients aged 31-60 and higher in those aged over 60 years old, and the risk also increased with a later year of diagnosis. Patients who were not white were at a higher risk of cardiovascular cause of death. Additionally, bilateral ovarian cancer and distant staging disease were linked to elevated risks of cardiovascular cause of death. Conclusion: Cardiovascular mortality is a significant concern in ovarian cancer patients, and several patient characteristics are associated with an increased risk. Our study suggests that targeted interventions to improve cardiovascular health in high-risk patients, such as those with comorbidities or an advanced stage at diagnosis, may improve survival in this population.

Insight into the architecture of the NuRD complex: structure of the RbAp48-MTA1 subcomplex.

The nucleosome remodeling and deacetylase (NuRD) complex is a widely conserved transcriptional co-regulator that harbors both nucleosome remodeling and histone deacetylase activities. It plays a critical role in the early stages of ES cell differentiation and the reprogramming of somatic to induced pluripotent stem cells. Abnormalities in several NuRD proteins are associated with cancer and aging. We have investigated the architecture of NuRD by determining the structure of a subcomplex comprising RbAp48 and MTA1. Surprisingly, RbAp48 recognizes MTA1 using the same site that it uses to bind histone H4, showing that assembly into NuRD modulates RbAp46/48 interactions with histones. Taken together with other results, our data show that the MTA proteins act as scaffolds for NuRD complex assembly. We further show that the RbAp48-MTA1 interaction is essential for the in vivo integration of RbAp46/48 into the NuRD complex.

Novel Mutation in Chromosome 11p15.4 Causing Niemann-Pick Disease Type A in a Saudi Child.

Niemann-Pick disease (NPD) encompasses a minimum of three lysosomal storage diseases, all of which are inherited in an autosomal recessive manner. Acid sphingomyelinase (ASM) deficiency is the cause of NPD types A and B. ASM is the enzyme that hydrolyzes the sphingolipid sphingomyelin. An 18-month-old patient with progressive painless abdominal distension with organomegaly and neurological deficits presented to our hospital. Brain imaging and laboratory findings did not show anything, but there was a millstone growth delay. The diagnosis of NPD type A was confirmed by a genetic examination, which revealed a twofold change on chromosome 11p15.4 in the region encoding the sphingomyelin phosphodiesterase-1 (SMPD1) gene. The patient was followed up with no specific treatment, and signs of respiratory infections were later reported.

Structural and free energy landscape analysis for the discovery of antiviral compounds targeting the cap-binding domain of influenza polymerase PB2.

Influenza poses a significant threat to global health, with the ability to cause severe epidemics and pandemics. The polymerase basic protein 2 (PB2) of the influenza virus plays a crucial role in the viral replication process, making the CAP-binding domain of PB2 an attractive target for antiviral drug development. This study aimed to identify and evaluate potential inhibitors of the influenza polymerase PB2 CAP-binding domain using computational drug discovery methods. We employed a comprehensive computational approach involving virtual screening, molecular docking, and 500 ns molecular dynamics (MD) simulations. Compounds were selected from the Diverse lib database and assessed for their binding affinity and stability in interaction with the PB2 CAP-binding domain. The study utilized the generalized amber force field (GAFF) for MD simulations to further evaluate the dynamic behaviour and stability of the interactions. Among the screened compounds, compounds 1, 3, and 4 showed promising binding affinities. Compound 4 demonstrated the highest binding stability and the most favourable free energy profile, indicating strong and consistent interaction with the target domain. Compound 3 displayed moderate stability with dynamic conformational changes, while Compound 1 maintained robust interactions throughout the simulations. Comparative analyses of these compounds against a control compound highlighted their potential efficacy. Compound 4 emerged as the most promising inhibitor, with substantial stability and strong binding affinity to the PB2 CAP-binding domain. These findings suggest that compound 4, along with compounds 1 and 3, holds the potential for further development into effective antiviral agents against influenza. Future studies should focus on experimental validation of these compounds and exploration of resistance mechanisms to enhance their therapeutic utility.

Association between polycystic ovary syndrome and the risk of malignant gynecologic cancers (ovarian, endometrial, and cervical): A population-based study from the U.S.A. National Inpatient Sample 2016-2019.

OBJECTIVE: This study aimed to systematically examine the relationship between polycystic ovary syndrome and ovarian, endometrial, and cervical cancers using the National Inpatient Sample (NIS) database. METHODS: We utilized the International Classification of Diseases (ICD-10) system to identify relevant codes from the NIS database (2016-2019). Univariate and multivariable regression analyses (adjusted age, race, hospital region, hospital teaching status, income Zip score, smoking, alcohol use, and hormonal replacement therapy) were conducted to evaluate association between PCOS and gynecologic cancers. Results were summarized as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: Overall, 15,024,965 patients were analyzed, of whom 56,183 and 14,968,782 patients were diagnosed with and without PCOS, respectively. Among the patients diagnosed with gynecologic cancers (n = 91,599), there were 286 with PCOS and 91,313 without PCOS. Univariate analysis revealed that PCOS was significantly associated with higher risk of endometrial cancer (OR = 1.39, 95 % CI [1.18-1.63], p < 0.0001), but lower risk of ovarian cancer (OR = 0.55, 95 % CI [0.45-0.67], p < 0.0001) and cervical cancer (OR = 0.68, 95 % CI [0.51-0.91], p = 0.009). In contrast, after Bonferroni correction, multivariable analysis depicted that PCOS remained significantly associated with higher risk of endometrial cancer (OR = 3.90, 95 % CI [4.32-4.59], p < 0.0001). There was no significant correlation between PCOS and risk of ovarian cancer (OR = 1.09, 95 % CI [0.89-1.34], p = 0.409) and cervical cancer (OR = 0.83, 95 % CI [0.62-1.11], p = 0.218). CONCLUSION: This first-ever NIS analysis showed that patients with PCOS exhibited unique gynecologic cancer risk profiles, with higher risk for endometrial cancer, and no significant risk for ovarian or cervical cancers.

Noncoding RNAs as therapeutic targets in autophagy-related diabetic cardiomyopathy.

Diabetic cardiomyopathy, a multifaceted complication of diabetes mellitus, remains a major challenge in clinical management due to its intricate pathophysiology. Emerging evidence underscores the pivotal role of autophagy dysregulation in the progression of diabetic cardiomyopathy, providing a novel avenue for therapeutic intervention. Noncoding RNAs (ncRNAs), a diverse class of regulatory molecules, have recently emerged as promising candidates for targeted therapeutic strategies. The exploration of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) reveal their intricate regulatory networks in modulating autophagy and influencing the pathophysiological processes associated with diabetic cardiomyopathy. The nuanced understanding of the molecular mechanisms underlying ncRNA-mediated autophagic regulation offers a rationale for the development of precise and effective therapeutic interventions. Harnessing the regulatory potential of ncRNAs presents a promising frontier for the development of targeted and personalized therapeutic strategies, aiming to ameliorate the burden of diabetic cardiomyopathy in affected individuals. As research in this field advances, the identification and validation of specific ncRNA targets hold immense potential for the translation of these findings into clinically viable interventions, ultimately improving outcomes for patients with diabetic cardiomyopathy. This review encapsulates the current understanding of the intricate interplay between autophagy and diabetic cardiomyopathy, with a focus on the potential of ncRNAs as therapeutic targets.

Association between Endometriosis and the Risk of Ovarian, Endometrial, Cervical, and Breast Cancer: A Population-Based Study from the U.S. National Inpatient Sample 2016-2019.

OBJECTIVE: We investigated the potential relationship between endometriosis and risk of ovarian, endometrial, cervical, and breast cancers using the National Inpatient Sample (NIS) database. METHODS: We utilized the International Classification of Diseases (ICD-10) system to identify relevant codes from the NIS database (2016-2019). Univariate and multivariate regression analyses (adjusted for age, race, hospital region, hospital teaching status, income Zip score, smoking, alcohol use, and hormonal replacement therapy) were conducted to evaluate the association between endometriosis and gynecologic cancers and summarized as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In the examined dataset, there were 1164 and 225,323 gynecologic cancer patients with and without endometriosis, respectively. Univariate analysis showed endometriosis was significantly associated with a higher risk of ovarian (OR = 3.42, 95% CI: 3.05-3.84, p < 0.001) and endometrial (OR = 3.35, 95% CI: 2.97-3.79, p < 0.001) cancers. There was no significant association between endometriosis and cervical cancer (OR = 1.05, 95% CI: 0.85-1.28, p = 0.663). Interestingly, endometriosis was significantly associated with a low risk of breast cancer (OR = 0.12, 95% CI: 0.10-0.17, p < 0.001). Multivariate analysis after Bonferroni correction (p < 0.006) showed that endometriosis was significantly associated with a high risk of ovarian (adjusted OR = 3.34, 95% CI: 2.97-3.75, p < 0.001) and endometrial (adjusted OR = 3.61, 95% CI: 3.12-4.08, p < 0.001) cancers. Conversely, there was no significant association between endometriosis and cervical cancer (OR = 0.80, 95% CI: 0.65-0.99, p = 0.036). CONCLUSIONS: Patients with endometriosis exhibited unique gynecologic cancer risk profiles, with higher risks for ovarian and endometrial cancers, and no significant risk for cervical cancer. The observed connection between endometriosis and a reduced risk of breast cancer remains a perplexing phenomenon, which cannot be put into context to date.

Parents' Knowledge, Attitude, and Practice Regarding Traditional Medicine on Their Children: A Community-Based Cross-Sectional Study in Bisha City, Saudi Arabia.

Background The use of traditional medicine (TM) in children is widespread, particularly in developing countries. Parents often rely on TM to treat their children's illnesses or maintain their health. However, the safety and efficacy of TM are often unclear, and there is a need to assess parents' knowledge, attitudes, and practices toward its use. Methods This is a community-based cross-sectional study conducted in Bisha, Saudi Arabia, with a sample size of 555. The study used a modified questionnaire to collect data. The data were collected from March to June 2023. This study involved both descriptive and inferential statistics.  Results The study included 555 participants, most of whom were female, Saudi nationals, and married and had a bachelor's degree. More than half of the participants reported using TM, and most believed that it had fewer side effects and could be taken with allopathic medicines. However, many participants did not believe that TM could prevent or cure all diseases or that it was always safe. The median knowledge score was 4.0, with higher scores associated with older age and higher educational level. Most participants had a positive attitude toward TM, with higher attitude scores associated with younger age, male gender, lower educational level, and healthcare-related occupation. The median practice score was 31.0, with higher scores associated with younger age, male gender, illiteracy, and healthcare-related occupation. Overall, the study highlights the importance of understanding the patterns of use, knowledge, attitudes, and practices of TM in the population, particularly among different demographic groups. Conclusions This study highlights the need for better regulation and supervision of TM outlets to ensure the safety and efficacy of the products. It also emphasizes the importance of consulting healthcare professionals before using TM on children. The findings suggest that healthcare providers should be knowledgeable about TM and provide guidance to parents on its appropriate use.

Nasopharyngeal Branchial Cleft Cyst: A Rare Case Report and Literature Review.

Branchial cleft cysts are birth defects that happen when the first through fourth pharyngeal clefts do not close properly and most of these cysts develop from the second cleft. Second branchial cleft cysts are almost always in the neck, so it is rare for them to present in the nasopharynx. We report an extremely rare case of a branchial cleft cyst that is located in an unusual site in the nasopharynx in a 36-year-old male with no prior medical history. Computed tomography scan findings showed non-enhancing thickening of the right side mucosal-pharyngeal space, obliterating the fossa of Rosenmuller with no invasion or erosion. The patient was admitted for nasopharyngeal mass excision, and the mass was sent for histopathology. When a cystic lesion is noted in the lateral nasopharynx, branchial cleft cysts should be on the list of possible diagnoses. Surgery is primarily the treatment. The marsupialization approach is a simple way to treat nasopharyngeal branchial cleft cysts as it is safe and has limited complications.

Evaluation of Perception, Awareness, and Practices Related to Burns First Aid: Largest Cross-Sectional Study Among Non-Healthcare Providers in the Western Region of Saudi Arabia.

Introduction Burn injuries are among the most catastrophic public health issues because of the severe physical, functional, and psychological effects. Numerous studies have revealed that both developed and developing societies lack understanding about first aid for burns. This research sought to review and appraise perception, awareness, and practices of burn first aid among non-healthcare providers in Jeddah, Saudi Arabia, and whether they need an effective program. To the best of our knowledge, this is likely the first research conducted in Jeddah. Methodology We conducted a cross-sectional study in Jeddah, Saudi Arabia using a self-administered online questionnaire among non-healthcare providers in July 2022. The questionnaire was made up of 29 questions divided into two sections: demographics and first aid for burns. The Unit of Biomedical Ethics Research Committee at the Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia approved this study. Results This study included 575 participants. Males comprised 54.8% (315) and females 45.2% (260) of all respondents. A total of 443 respondents (77%) held a university diploma. All respondents had a mean burn knowledge score of 6.35±1.43 out of eight. Traditional medication was used on the burn by 484 people (84.2%). Antibiotic use in burn injuries was poorly understood as 453 (78.8%) of study participants agreed that antibiotics are beneficial in the case of burns, which is incorrect. Conclusion The level of first-aid practices for burn patients among non-healthcare workers was insufficient, and the use of traditional medicines and antibiotics in burn patients was excessive. The findings of this study should be carefully considered by various healthcare organizations.

Primary hyperparathyroidism associated with colorectal cancer: case report.

The association between colorectal cancer and primary hyperparathyroidism has been reported as case reports in the literature. There are few data regarding the molecular explanation of such coexistence. Here we report a case with synchronous pathologies of primary hyperparathyroidism and colorectal cancer. Furthermore, the patient has a positive family history of the same two pathologies in one of his first-degree relatives. We reviewed the literature to clarify and explain the relationship between these two diseases. We aimed to shed light on the coexistence of such conditions and to clarify if there is a relation between them or if it is just a coincidence.

Prevalence and Patterns of Refractive Error Among School-Age Children in Bisha, Saudi Arabia.

BACKGROUND: A widespread and serious eye condition is a refractive error (RE). Globally, uncorrected refractive defects affect numerous individuals, with some who are blind. Numerous studies in Saudi Arabia have been conducted to assess reflective error. However, there is a lack of knowledge regarding RE among school-age children in Bisha province, southwest Saudi Arabia. This study aimed to determine the prevalence and types of RE among school-age children in Bisha, Saudi Arabia. METHODS: A cross-sectional study involved 360 schoolchildren from primary schools was carried out between December 2022 and November 2023 in Bisha. A validated questionnaire form was used to collect sociodemographic information and clinical data (history of the ocular problem, visual acuity test findings, and the refractor machine's result). RESULT: A total of 360 schoolchildren aged from seven to 14 years, with a mean of 10.1 years (standard deviation (SD)=2.05). The prevalence of hyperopia was 21% in the right eye and 23% in the left eye. In addition, the prevalence of myopia was 20% in the right eye and 22.5% in the left eye. A significant association between visual acuity and myopia (p=0.001). By contrast, there was no significant correlation between hyperopia and visual acuity (p=0.412). CONCLUSION: The current study summarized the prevalence of REs among school-age children in Bisha, Saudi Arabia. The study population included nearly half of those with at least some degree of RE. These results highlight the need for prompt and careful screening programs to detect and treat refractive disorders across this age range.

Insights into association of the NuRD complex with FOG-1 from the crystal structure of an RbAp48·FOG-1 complex.

Chromatin-modifying complexes such as the NuRD complex are recruited to particular genomic sites by gene-specific nuclear factors. Overall, however, little is known about the molecular basis for these interactions. Here, we present the 1.9 Å resolution crystal structure of the NuRD subunit RbAp48 bound to the 15 N-terminal amino acids of the GATA-1 cofactor FOG-1. The FOG-1 peptide contacts a negatively charged binding pocket on top of the RbAp48 ß-propeller that is distinct from the binding surface used by RpAp48 to contact histone H4. We further show that RbAp48 interacts with the NuRD subunit MTA-1 via a surface that is distinct from its FOG-binding pocket, providing a first glimpse into the way in which NuRD assembly facilitates interactions with cofactors. Our RbAp48·FOG-1 structure provides insight into the molecular determinants of FOG-1-dependent association with the NuRD complex and into the links between transcription regulation and nucleosome remodeling.

Quality of care provided to diabetic patients attending primary health care centers in National Guard in Makkah Region, Saudi Arabia.

Background: Diabetes is a costly and serious health problem that is increasing markedly. The quality of care is a major issue among diabetic patients. This study aims to assess the quality of care provided to diabetic patients using the American Diabetes Association (ADA) indicators. Methods: This was a cross-sectional study conducted using a retrospective chart review. The population was adult diabetic patients (type 2) who had attended the National Guard's primary healthcare centers, Makkah region, Saudi Arabia, from January 1, 2017, to December 31, 2018. Results: We studied 400 adult diabetic patients aged 30-97 years with a mean age of 58.25 (SD = 11.9). The length of time with diabetes ranged from 1 to 42 years with a mean of 9.66 years (SD = 7.6). Among all the primary healthcare centers (PHCs), specialized polyclinic (SPC) had the highest number of patient visits. Furthermore, the SPC had the highest number of patients with complications; the primary healthcare center with the fewest complications was Iskan-Jeddah. The results show that the control of hemoglobin A1C (HbA1C) was better in 2018 than in 2017. Conclusion: There is improved and adequate care provided to patients among the assessed primary healthcare centers in the Makkah region. Nevertheless, there remains a need for interventions to maintain comprehensive data on diabetes performance. Monitoring and proper education on diabetic care to patients are suggested to achieve better control of diabetes and delay the occurrence of complications.

Complete Laryngotracheal Separation Secondary to Blunt Trauma: A Case Report.

Complete laryngotracheal separation is a rare life-threatening trauma that may occur due to road traffic accidents. Unfortunately, this injury may be missed if emergency physicians were not aware of its possibility. We present a pediatric patient who had complete laryngotracheal separation and esophageal injury caused by strangulation with a headscarf while riding a four-wheeled motorcycle. The neck on external examination showed only a ligature mark without open wounds. The injury was identified while attempting tracheostomy as the patient had a decreased oxygen saturation and was aphonic. The patient underwent complete airway reconstruction and stenting as well as low tracheostomy with complete reconstruction and anastomosis of the esophagus. The patient was decannulated after a few weeks with the vocal cords in paramedian position and no aspiration. This case demonstrates that early prompt treatment can save the patient's life and result in good functional outcomes.

Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity.

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.

Synthesis, Optimization, and Structure-Activity Relationships of Imidazo[1,2-a]pyrimidines as Inhibitors of Group 2 Influenza A Viruses.

The influenza A virus (IAV) is a highly contagious virus that causes pandemics and seasonal epidemics, which are major public health issues. Current anti-influenza therapeutics are limited partly due to the continuous emergence of drug-resistant IAV strains; thus, there is an unmet need to develop novel anti-influenza therapies. Here, we present a novel imidazo[1,2-a]pyrimidine scaffold that targets group 2 IAV entry. We have explored three different regions of the lead compound, and we have developed a series of small molecules that have nanomolar activity against oseltamivir-sensitive and -resistant forms of group 2 IAVs. These small molecules target hemagglutinin (HA), which mediates the viral entry process. Mapping a known small-molecule-binding cavity of the HA structure with resistant mutants suggests that these molecules bind to that cavity and block HA-mediated membrane fusion.