Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.

Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents.

We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For this study we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect against sphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell line tested, with GI50 below 5 µM, being (5) the most promising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study about the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.

Update on premature physeal closure. Diagnosis and treatment.

PURPOSE OF REVIEW: Premature Physeal Closure (PPC) is the most common consequence of a mostly posttraumatic, physeal injury. They are of utmost importance because they can significantly alter physeal function and lead to disorders such as limb length discrepancies and angular deformities. RECENT FINDINGS: The type of physeal fracture has not demonstrated a solid predictive value in the formation of PPC, especially in the knee where almost any type of fracture can produce it. The detection of physeal damage with imaging tests (simple radiology and MRI) is very accurate; however, their predictive capacity to foretell which injury will generate a physeal bridge is still poor. For this reason, it is not advisable to make surgical decisions at the first medical assessment. Direct surgical management of PPC's (resection-interposition technique) has generally shown high unpredictability. Nevertheless, the latest interposition materials (chondrocytes and mesenchymal stem cells) showed promising results. SUMMARY: PPC is an often devastating consequence of physeal injury and as such deserves further research. To date little is known about etiopathogenesis, risk factors and natural history among other aspects. Until direct surgery offers more consistent results, acute osteotomies and bone distraction for progressive correction continue to be the most widespread treatments for PPCs.

Multicomponent intervention provided by GPs to reduce cardiovascular risk factors: evaluation in an Italian large sample.

BACKGROUND: The cardiovascular risk increases in a multiplicative way when patients present more risk factors simultaneously. Moreover, the General Practitioners (GPs) play a crucial role in risk factors prevention and reduction. This work aimed to evaluate a multicomponent intervention in the Primary Care Department in an Italian Local Health Unit. METHODS: A pre-post study was conducted in Northern Italy (2018). Patients were eligible if: aged between 30 and 60 years, not chronic patients, not affected by hypertension or hypercholesterolaemia. The GPs assessed body mass index, hypertension, abdominal obesity, low-density lipoprotein (LDL) values, glycaemic values, smoking and exercise habit (T0). A counselling by GPs to at-risk patients and a multicomponent health education intervention were performed. Reassessment occurred after at least 3 months (T1). Main analyses were chi-squared tests for gender differences, McNemar or marginal homogeneity tests for changes in paired data (P < 0.05 as significant). RESULTS: Participants were 5828 at T0 (54.0% females) and 4953 at T1 (53.4% females). At T0, 99.1% presented at least one risk factor. Significant changes in paired data were reported for each risk factor. The greatest improvement frequencies occurred in glycaemia values (51.0%) and hypertension (45.6%), the lowest in abdominal obesity (3.7%). Some differences were recorded between genders, e.g. females reported higher improvement frequencies in hypertension (P = 0.001) and abdominal obesity (P < 0.001), whereas males in physical activity (P = 0.011) and LDL values (P = 0.032). CONCLUSION: The results showed significant changes for each risk factor, both for men and women. GPs and multicomponent educational interventions could play a key role in reducing cardiovascular risk factors.

Upper Limb Lengthening in Achondroplasia Using Unilateral External Fixation.

PURPOSE: The purpose of this study was to analyze the long-term results of humeral lengthening in achondroplastic patients and make suggestions on the most appropriate surgical technique to improve patient outcomes. METHODS: Fifty-four humeral lengthening procedures performed in 27 achondroplastic patients were reviewed. Elongations were performed by means of callotasis with unilateral external fixation. Inclusion criteria were: achondroplastic patients under 17 years without prior arm operations and minimum follow-up of 36 months. RESULTS: Fifty humeri in 25 patients (13 men and 12 women), aged between 9 and 17 years, met the inclusion criteria. Mean humeral lengthening was 8.82 cm (range: 5 to 10.5 cm), which represented an elongation of 54.80% (range: 46% to 63%) of the original length. The healing index was 0.91 months (range: 0.72 to 1.4 mo) per centimeter gained. Shoulder and elbow range of motion and stability were preserved in 47 limbs. Noncomplicated cases consistently experienced a significant functional improvement in the performance of activities of daily living such as putting on footwear and personal hygiene. Short-term complications included 11 pin-tract infections, 1 radial nerve neuropraxia, and 1 failure of the regenerated bone formation. None of these complications prevented from completion of treatment. Long-term complications included 2 cases of nonunion, 3 elbow flexion contractures, and 2 cases of psychological dissatisfaction, all of them in 4 patients. Factors associated with long-term complications were intraoperative fragment displacement and distal humeral osteotomy. No fractures of the regenerated bone were identified in the long term. CONCLUSIONS: Callotasis with unilateral external fixation is a reliable and well-tolerated procedure for humeral lengthening in achondroplastic patients, with an acceptable complication rate. Guided fixator placement and a proximal humeral osteotomy are strongly recommended technical tips as they may help prevent complications and improve outcomes. LEVEL OF EVIDENCE: Level IV-case series.

Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors.

Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails. On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that stabilize the different complexes of these new inhibitors with the active sites of the SphK1. This information will be useful in the design of new SphK inhibitors.

Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation.

Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1-16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1-3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.

Update on treatment of adolescent Blount disease.

PURPOSE OF REVIEW: Treatments available to correct adolescent Blount disease deformities differ in terms of features, advantages, and disadvantages. Each is indicated, therefore, for different scenarios of severity, physeal condition, and maturity. The purpose of this review is to update basic concepts, surgical treatments, and controversies concerning this disorder. RECENT FINDINGS: The cause of Blount disease is unknown although etiologic factors as morbid obesity and hypovitaminosis D are thought to be associated with it. Recently, semiinvasive techniques (guided growth) have been proposed for mild deformities but remain controversial. Osteotomies with external fixation (hexapodes) are still the most recommended corrective treatment in this condition. SUMMARY: Little is known about the origin and natural history of Blount disease. Treatment is always surgical and, given their complexity, should be preceded by a thorough analysis and planning regarding all deformities. Treatment principles are to correct the three-dimensional deformity and avoid recurrence. The choice of technique mainly depends on patient maturity and severity. Guided growth is a good choice for more immature patients with moderate deformities. Progressive correction using osteotomy or physeal distraction is indicated for patients with severe deformities and low remaining growth. The Taylor spatial frame is currently the most popular progressive correction device.

Theoretical models to predict the inhibitory effect of ligands of sphingosine kinase 1 using QTAIM calculations and hydrogen bond dynamic propensity analysis.

We report here the results of two theoretical models to predict the inhibitory effect of inhibitors of sphingosine kinase 1 that stand on different computational basis. The active site of SphK1 is a complex system and the ligands under the study possess a significant conformational flexibility; therefore for our study we performed extended simulations and proper clusterization process. The two theoretical approaches used here, hydrogen bond dynamics propensity analysis and Quantum Theory of Atoms in Molecules (QTAIM) calculations, exhibit excellent correlations with the experimental data. In the case of the hydrogen bond dynamics propensity analysis, it is remarkable that a rather simple methodology with low computational requirements yields results in excellent accord with experimental data. In turn QTAIM calculations are much more computational demanding and are also more complex and tedious for data analysis than the hydrogen bond dynamic propensity analysis. However, this greater computational effort is justified because the QTAIM study, in addition to giving an excellent correlation with the experimental data, also gives us valuable information about which parts or functional groups of the different ligands are those that should be replaced in order to improve the interactions and thereby to increase the affinity for SphK1. Our results indicate that both approaches can be very useful in order to predict the inhibiting effect of new compounds before they are synthesized.

New ATP-competitive inhibitors of E. coli GyrB obtained from the mapping of the hydrophobic floor at the binding site: synthesis and biological evaluation.

We mapped the hydrophobic floor, an interesting subsite at the active site of DNA gyrase B (GyrB) from E. coli. We synthesized three new compounds with pendant groups targeting the hydrophobic floor and evaluated their inhibitory activities on DNA gyrase. A new benzothiazole derivative with a benzyl substituent at position 3 of the benzothiazole ring exhibited strong inhibitory activity against E. coli DNA gyrase (IC50 = 19 ± 3 nM). An exhaustive conformational study using potential energy surfaces (PESs) allowed us to map the new subsite evaluating all critical points on the surface and conformational interconversion pathways. We analyzed the molecular interactions using QTAIM calculations. Our data provide insights into the mechanism of action of these new ligands at the molecular level. Theoretical and experimental data suggest that new ligand optimization strategies should focus on strengthening interactions at the hydrophobic floor while preserving the binding mode of the main scaffold.

Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration.

A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.

Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents.

A library of structurally related coumarins was generated through synthesis reactions and chemical modification reactions to obtain derivatives with antiproliferative activity both in vivo and in vitro. Out of a total of 35 structurally related coumarin derivatives, seven of them showed inhibitory activity in in vitro tests against Taq DNA polymerase with IC50 values lower than 250 µM. The derivatives 4-(chloromethyl)-5,7-dihydroxy-2H-chromen-2-one (2d) and 4-((acetylthio)methyl)-2-oxo-2H-chromen-7-yl acetate (3c) showed the most promising anti-polymerase activity with IC50 values of 20.7 ± 2.10 and 48.25 ± 1.20 µM, respectively. Assays with tumor cell lines (HEK 293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (2c) was the most promising, with an IC50 value of 8.47 µM and a selectivity index of 1.87. In addition, the derivatives were evaluated against Saccharomyces cerevisiae strains that report about common modes of actions, including DNA damage, that are expected for agents that cause replicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)-2H-chromen-2-one (5b) and 7-(3-(oxiran-2-yl)propoxy)-2H-chromen-2-one (5c) caused DNA damage in S. cerevisiae. The O-alkenylepoxy group stands out as that with the most important functionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the in vitro antiretroviral capacity was tested through RT-PCR assays. Derivative 5c showed inhibitory activity below 150 µM with an IC50 value of 134.22 ± 2.37 µM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.

Atraumatic Anterior Hip Dislocation as High Grade of Hip Instability: A Case Report.

CASE: Fifty-year-old woman who presented an atraumatic anterior hip dislocation during a local traditional dance exhibition. The dislocation occurred during a dance step in which extreme hip position in extension and external rotation was held. After urgent closed reduction under general anesthesia, the patient underwent conservative management with a follow-up of 24 months. There were no further dislocation events or sequelae, with the Hip Disability and Osteoarthritis Outcome Score-12 scale score was 100 points at the end of follow-up. CONCLUSIONS: Atraumatic hip dislocation is the highest grade and exceptional presentation of hip instability and requires immediate treatment. Conservative treatment is satisfactory, although in case of recurrence or persistent residual symptoms, other treatments are warrant.

Strategies targeting FLT3 beyond the kinase inhibitors.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion and differentiation arrest of the myeloid progenitor cells, which leads to the accumulation of immature cells called blasts in the bone marrow and peripheral blood. Mutations in the receptor tyrosine kinase FLT3 occur in 30% of normal karyotype patients with AML and are associated with a higher incidence of relapse and worse survival. Targeted therapies against FLT3 mutations using small-molecule FLT3 tyrosine kinase inhibitors (TKIs) have long been investigated, with some showing favorable clinical outcomes. However, major setbacks such as limited clinical efficacy and the high risk of acquired resistance remain unresolved. FLT3 signaling, mutations, and FLT3 inhibitors are topics that have been extensively reviewed in recent years. Strategies to target FLT3 beyond the small molecule kinase inhibitors are expanding, nevertheless they are not receiving enough attention. These modalities include antibody-based FLT3 targeted therapies, immune cells mediated targeting strategies, and approaches targeting downstream signaling pathways and FLT3 translation. Here, we review the most recent advances and the challenges associated with the development of therapeutic modalities targeting FLT3 beyond the kinase inhibitors.

Prospective study of pediatric medial humeral epicondyle fractures nonoperatively treated. Clinical, radiologic, and functional evaluation at long term.

The objective of the study is to evaluate the natural history of the medial epicondyle avulsion in children with nonoperative treatment (NOPT) on different magnitude of displacement and long-term follow-up. A prospective study of 34 patients with medial epicondyle avulsion with (NOPT) was performed. Clinical test (stability, strength, atrophy, tenderness, Tinel test, and range of motion), subjective scores [Visual Analog Scale (VAS), Likert scale, side-to-side valgus test], and objective four scores were performed. Age at the time of injury was 8.9 ± 2.81 years. Follow-up was 7 ± 2.81 years. Four of the patients had anterior displacement. Displacement varied between 3 and 26 mm (10.49 ± 6.16 mm). Subjective: VAS and ordinal three-point Likert scale were excellent. Objective results were also excellent Mayo Elbow Score: 98.67 ± 4.31 (85-100), Oxford Elbow Score: 59.35 ± 1.68 (51-100), Elbow Assessment Score System: 96.27 ± 9.77 (57-100), Disabilities of the Arm, Shoulder, and Hand (DASH) score 0.64 ± 1.001 (0-4.16). We did not find any differences in strength or forearm diameter. There was an extension deficit in seven cases with a significant association with the magnitude of displacement (P = 0.02) and with the presence of concomitant lesions or anterior displacement of the medial epicondyle >5 mm. All except one were stable clinically on valgus stress. There is a significant association between the objective outcomes (scores) and concomitant lesions but not with regards to the DASH score P = 0.102). There is no association between the magnitude of medial epicondyle displacement or the follow-up and the objective outcomes. Instability was associated with valgus stress activities. There is no association between the magnitude of displacement of the medial epicondyle or the follow-up and the objective outcomes. NOPT produces excellent subjective and objective outcomes that worsened when there were associated lesions, anterior medial epicondyle displacement, or in patients who performed activities with repeated valgus stress. Based on our study, NOPT is suitable except for Open Reduction Internal Fixation indications: absolute indications, high energy injury with associated lesions, medial humeral epicondyle fracture in the dominant elbow in patients subject to activities with chronic valgus stress, and anterior displacement.

Salvage Procedures of the Shoulder: Glenohumeral Arthrodesis and Resection Arthroplasty.

BACKGROUND: With the advances of modern medicine and technology there has been an increase of indications of shoulder reconstruction techniques and shoulder arthroplasty. Consequently, the number of complications and failures have increased in parallel. Not negligible number of cases are driven to an end-stage situation where salvage procedures, such as glenohumeral arthrodesis (GHA) and shoulder resection arthroplasty (SRA), are the only remaining solution. METHODS: The current literature on glenohumeral arthrodesis and shoulder resection arthroplasty was reviewed to determine the indications, surgical technique, complications and outcomes. The electronic search was conducted using the MEDLINE and EMBASE databases and the strategies used were "glenohumeral arthrodesis", "glenohumeral fusion", "shoulder arthrodesis" and "shoulder resection arthroplasty". RESULTS: Indications for glenohumeral arthrodesis (GHA) include brachial plexus injury, tumor resections, chronic infection, failed prosthetic arthroplasty, persistent refractory instability or pseudoparalysis of the shoulder with combined irreparable rotator cuff and deltoid injuries. GHA provides good stability, pain resolution, although function is markedly compromised and relying mostly on scapulothoracic joint. The gold standard surgical technique continues to be open shoulder arthrodesis and still has a high complication rate. Shoulder resection arthroplasty (SRA) indications have evolved through the years, being nowadays a salvage procedure for recalcitrant infection of shoulder arthroplasty the main indication. Shoulder function after SRA is often severely compromised, but has a high infection rate resolution. SRA is not technically demanding and complications are rare, being the persistence of infection the most common one. DISCUSSION: Despite GHA and SRA having negative connotations, in selected patients, these procedures can diminish pain, resolve persistent infections and provide an acceptable shoulder function. Hence, they should be retained as part of the treatment algorithm for complex shoulder pathology.

Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: a molecular modeling approach.

We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within 6 Å from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1−INH complex.

Deciphering the TCR Repertoire to Solve the COVID-19 Mystery.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected several millions and killed more than quarter of a million worldwide to date. Important questions have remained unanswered: why some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection. Here, we discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of the disease, COVID-19. We highlight the scientific rationale for comprehensive and longitudinal TCR analyses in COVID-19 and reason that analyzing TCR repertoire in COVID-19 patients would reveal important findings that may explain the outcome disparity observed in these patients. Finally, we provide a framework describing the different strategies, the advantages, and the challenges involved in obtaining useful TCR repertoire data to advance our fight against COVID-19.

Aporphinoid Alkaloids Derivatives as Selective Cholinesterases Inhibitors: Biological Evaluation and Docking Study.

Alzheimer's dementia is a neurodegenerative disease that affects the elderly population and causes memory impairment and cognitive deficit. Manifestation of this disease is associated to acetylcholine decrease; thus, Cholinesterase inhibition is the main therapeutic strategy for the treatment of Alzheimer's disease. In the present study, a series of aporphinoid alkaloids were tested as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors in vitro. Alkaloids liriodenine (3) and cassythicine (10) were the best inhibitors of both cholinesterases with IC50 values lower than 10 µM. In addition, these alkaloids demonstrated better inhibition of BChE than reference drug galantamine. In addition, some alkaloids showed selective inhibition. Laurotetatine clorhydrate (13) selectively inhibit AChE over BChE. On the contrary, pachyconfine (7) interacted more efficiently with BChE active site. Molecular modelling studies were performed in order to illustrate key interactions between most active compounds and the enzymes and to explain their selectivity. These studies reveal that the benzodioxole moiety exhibits strong interactions due to hydrogen bonds that form with the Glu201 (AChE) and Tyr440 (BChE) residues, which is reflected in the IC50 values.

The Confluence of Innovation in Therapeutics and Regulation: Recent CMC Considerations.

The field of human therapeutics has expanded tremendously from small molecules to complex biological modalities, and this trend has accelerated in the last two decades with a greater diversity in the types and applications of novel modalities, accompanied by increasing sophistication in drug delivery technology. These innovations have led to a corresponding increase in the number of therapies seeking regulatory approval, and as the industry continues to evolve regulations will need to adapt to the ever-changing landscape. The growth in this field thus represents a challenge for regulatory authorities as well as for sponsors. This review provides a brief description of novel biologics, including innovative antibody therapeutics, genetic modification technologies, new developments in vaccines, and multifunctional modalities. It also describes a few pertinent drug delivery mechanisms such as nanoparticles, liposomes, coformulation, recombinant human hyaluronidase for subcutaneous delivery, pulmonary delivery, and 3D printing. In addition, it provides an overview of the current CMC regulatory challenges and discusses potential methods of accelerating regulatory mechanisms for more efficient approvals. Finally, we look at the future of biotherapeutics and emphasize the need to bring these modalities to the forefront of patient care from a global perspective as effectively as possible.