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This meta-analysis aimed to ascertain whether small molecule drugs increase the risk of infection or malignancy in adult IBD patients. A comprehensive search of eight databases was conducted from their inception to November 2023. The risk of infections or malignancies in adult IBD patients treated with JAK inhibitors and S1P receptor modulators was compared. Fixed-effects or random-effects models were performed, and relative risk (RR) and 95 % confidence interval (CI) were calculated. 27 RCTs from 14 studies were included (n = 10,623). The evidence indicates that small molecule drugs increase the risk of any infections (RR: 1.23, 95 %CI: 1.05–1.44) and herpes zoster (RR: 2.23, 95 %CI: 1.39–3.57). Specifically, UC patients on Filgotinib and Tofacitinib, and CD patients on Upadacitinib, showed elevated risks of any infections (RR: 1.27, 95 % CI: 1.04–1.56; RR: 1.42, 95 % CI: 1.16–1.75; RR: 1.57, 95 % CI: 1.11–2.22). CD patients on Upadacitinib also had a significantly higher risk of herpes zoster (RR: 2.64, 95 %CI: 1.16–5.99). No infections were associated with S1P receptor modulators, and similarly, no malignancies were linked to small molecule drugs. JAK inhibitors increase the risk of any infections and herpes zoster Over a one-year follow-up period in IBD patients. Continuous monitoring of their long-term safety is necessary. [ABSTRACT FROM AUTHOR]

Viruses have long been a significant threat to human survival and development, with recent events such as the COVID-19 pandemic vividly highlighting their dangers. Small molecule drugs have historically played a crucial role in humanity's efforts to combat diseases. In the fight against viruses, humans have developed a range of strategies, with small molecule antiviral drugs occupying a pivotal position. Drawing inspiration from the classic "Thirty-Six Stratagems" of ancient Chinese military tactics, this article provides a concise overview of the developmental history of small molecule antiviral drugs, focusing on the design principles and mechanisms of representative drugs like idoxuridine, saquinavir, and oseltamivir. Furthermore, the article provides insights into future directions for small molecule antiviral drugs and antiviral methodologies. [ABSTRACT FROM AUTHOR]

Background Ulcerative colitis (UC) is a persistent immune-mediated inflammatory bowel disease characterized by chronic relapses and remissions. The management of UC remains a subject of contention, particularly as approximately half of the patients experience a complex disease progression marked by chronic activity or frequent recurrence of common UC symptoms, significantly impacting their quality of life. Objective The current landscape presents a growing array of treatment modalities for UC. This study aims to systematically compare the relative efficacy and safety of biologics and small molecule drugs in treating patients with UC. Methods Two independent researchers meticulously conducted a search for randomized controlled trials involving biologics and small molecule drugs for UC. The search encompassed PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang Data, and VIP. The intervention group involved either biologics or small molecule drugs, while the control group received a placebo. The quality of the included studies was assessed using the Cochrane Risk of Bias tool and RevMan 5.4. Paired analyses and network meta-analyses were conducted using R Studio. The surface under the cumulative ranking curve (SUCRA) was employed to rank the included drugs based on each outcome indicator, providing a comparative assessment of the clinical efficacy of diverse treatments for UC. Results A total of 25 studies including 9 546 patients with ulcerative colitis and 10 intervention regimens (Filgotinib 100 mg, Filgotinib 200 mg, Upadacitinib, Tofacitinib, Etrolizumab, Adalimumab, Vedolizumab, Golimumab 50 mg, Golimumab 100 mg, Infliximab). The results of SUCRA probability ranking of clinical remission effect of each drug showed that Upadacitinib (94.1%) >Vedolizumab (85.1%) >Tofacitinib (74.3%) >Infliximab (72.7%) >Filgotinib 200 mg (51.5%) >Golimumab 100 mg (44.3%) >Golimumab 50 mg (39.3%) >Etrolizumab (38.9%) >Adalimumab (29.8%) >Filgotinib 100 mg (18.7%) >Placebo (0.7%). The results of SUCRA probability ranking of the effect of each drug on clinical response showed that Upadacitinib (98.4%) >Infliximab (84.4%) >Tofacitinib (67.2%) >Vedolizumab (58.4%) >Golimumab 50 mg (53.3%) >Adalimumab (34.6%) >Golimumab 100 mg (30.1%) >Placebo (0.4%). The results of SUCRA probability ranking of the effect of each drug on endoscopic remission showed that Upadacitinib (98.7%) >Tofacitinib (68.6%) >Filgotinib 200 mg (59.6%) >Adalimumab (55.2%) >Etrolizumab (46.0%) >Vedolizumab (45.9%) >Filgotinib 100 mg (23.4%) >Placebo (2.2%). The results of SUCRA probability ranking of the effect of each drug on mucosal healing showed that Upadacitinib (99.7%) >Tofacitinib (77.2%) >Infliximab (65.2%) >Golimumab 50 mg (46.4%) >Vedolizumab (44.4%) >Adalimumab (33.8%) >Golimumab 100 mg (31.9%) >Placebo (1.0%). The results of the SUCRA probability ranking of the risk of adverse events for each drug showed that Golimumab 100 mg (96.7%) >Golimumab 50 mg (92.1%) >Placebo (68.7%) >Tofacitinib (60.8%) >Adalimumab (60.7%) >Etrolizumab (47.2%) >Upadacitinib (42.2%) >Vedolizumab (41.3%) >Infliximab (27.0%) >Filgotinib 200 mg (6.6%) >Filgotinib 100 mg (6.2%) . Conclusion Upadacitinib demonstrated optimal efficacy in clinical response, clinical remission, mucosal healing, and endoscopic remission, and Filgotinib 100 mg demonstrating safer outcomes in terms of adverse events.

Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators are small molecule drugs (SMDs) approved for IBD treatment. Their use in clinical practice might be limited due to cardiovascular concerns. We aimed to provide guidance on risk assessment, monitoring, and management strategies, aiming to minimize potential cardiovascular risks of SMDs and to facilitate an adequate shared decision-making. A systematic literature search was conducted, and proposed statements were prepared. A virtual consensus meeting was held, in which eleven IBD physicians and two cardiovascular specialists from ten countries attended. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75 % of participants voting as 'agree' with each statement. Consensus was reached for eighteen statements. Available evidence does not show a higher risk of cardiovascular events with JAK inhibitors in the overall IBD population, although it might be increased in patients with an unfavorable cardiovascular profile. S1P receptor modulators may be associated with a risk of bradycardia, atrioventricular blocks, and hypertension. Cardiovascular risk stratification should be done before initiation of SMDs. Although the risk of cardiovascular events in patients with IBD on SMDs appears to be low overall, caution should still be taken in certain scenarios. [ABSTRACT FROM AUTHOR]

Lichen amyloidosis (LA) is a predominant type of primary cutaneous amyloidosis that is characterized by persistent and intense skin itching. Although multiple therapeutics strategies are available for its treatment, there is no standard treatment so far. Abrocitinib, an oral small-molecule Janus kinase 1 inhibitor, has been authorized for the treatment of severe atopic dermatitis (AD) and can also provide rapid relief from pruritus. Here, we discuss the case of a 32-year-old man who was diagnosed with LA with severe AD based on the presence of multiple, discrete, and hyperpigmented papules and pruritic, erythematous macules with lichenification of the limbs, trunk, and buttocks. Given the inefficacy of conventional therapy, abrocitinib treatment was recommended in this patient. After 1 month of treatment, the patient’s Eczema Area And Severity Index score decreased significantly from 48 to 15 points, accompanied by a notable reduction in pruritus symptoms. Furthermore, significant improvements were observed in the thickness and pigmentation of the hyperkeratotic papules. Thus, abrocitinib exhibited excellent effectiveness and safety in the treatment of severe AD with LA and warrants further investigation for its potential therapeutic benefits.

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.

Patients with atopic dermatitis (AD) have skin barrier dysfunction, which is closely related to keratinocyte (KC) abnormalities. Upon stimulation by external factors, KCs release a large number of inflammatory mediators, thereby activating type 2 inflammation, which, in turn, exacerbates skin barrier dysfunction. Thus, the interaction between KCs and type 2 inflammation is a key factor in the pathogenesis of AD, and exacerbation of inflammation and pruritus. At present, the innovative medications, such as biologics and small molecule drugs, have been shown anti-inflammatory effects in AD. Studies also demonstrate their role in skin barrier repair. Therefore, research on the interaction between KCs and type 2 inflammation will help understand the pathogenesis of AD and provide evidence to optimize treatment strategies for AD.

Snakebite envenoming results in ~100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Nextgeneration snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)--a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-tolead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules. [ABSTRACT FROM AUTHOR]

Patients with atopic dermatitis (AD) have skin barrier dysfunction, which is closely related to keratinocyte (KC) abnormalities・ Upon stimulation by external factors, KCs release a large number of inflammatory mediators, thereby activating type 2 inflammation, which, in turn, exacerbates skin barrier dysfunction・ Thus, the interaction between KCs and type 2 inflammation is a key factor in the pathogenesis of AD, and exacerbation of inflammation and pruritus・ At present, the innovative medications, such as biologies and small molecule drugs, have been shown anti-inflammatory effects in AD・ Studies also demonstrate their role in skin barrier repair. Therefore, research on the interaction between KCs and type 2 inflammation will help understand the pathogenesis of AD and provide evidence to optimize treatment strategies for AD. [ABSTRACT FROM AUTHOR]

China recently proposed a 6-year regulatory exclusivity period to incentivize research and development in new drugs, orphan drugs, and pediatric drugs. Our study assessed the generic entry status and the duration of market exclusivity for 356 new small-molecule drugs approved in China from 2003 to 2020. Of these, 155 drugs (43.5%) experienced generic entry, with a median market exclusivity period of 5.6 years (interquartile range: 2.4-9.4). Imported drugs, oral common-release agents, and drugs for the nervous system were more prone to generic entry (P < 0.001, P = 0.039, and P < 0.001, respectively). Domestic new drugs had a longer median market exclusivity (8.4 years) compared to imported drugs (5.7 years). Market exclusivity varied from 3.6 years for antineoplastic and immunomodulating agents to 6.8 years for drugs for the alimentary tract and metabolism. If the proposed 6-year regulatory exclusivity is implemented, the market exclusivity duration for new drugs is anticipated to double. It is essential for the government to carefully weigh the impact of such policies on balancing innovation incentives and ensuring drug affordability. [ABSTRACT FROM AUTHOR]

Abstract The tumor microenvironment (TME) is the ecosystem surrounding a tumor, which usually consists of nontumoral cells or components, and molecules they produce and release. The frequent and continuous interplay between tumor cells and the TME strongly affects tumor development, disease progression, metastasis, and responses to therapeutic interventions. As a hub of potential therapeutic targets, the TME has gained appreciable momentum in cancer research. Here we systematically review the progress in targeting the TME as a strategy to develop novel antitumor drugs from the immunological, stromal and extracellular matrix components of the TME, shedding light on its complex synergies with tumor cells. This exploration highlights the transformative potential these elements hold in refining cancer treatment approaches. This thorough examination not only accentuates the TME's multifaceted nature but also positions it as a formidable avenue for propelling forward the paradigms of cancer therapy. This review aims to foster a deeper understanding of the TME's role in oncogenesis and its potential exploitation in advancing targeted, efficacious cancer treatments, marking a significant stride in the realm of cancer research.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis. The number of cases increased by 2.26 million in 2020, making it the most commonly diagnosed cancer type in the world. TNBCs lack hormone receptor (HR) and human epidermal growth factor 2 (HER2), which limits treatment options. Currently, paclitaxel-based drugs combined with other chemotherapeutics remain the main treatment for TNBC. There is currently no consensus on the best therapeutic regimen for TNBC. However, there have been successful clinical trials exploring large-molecule monoclonal antibodies, small-molecule targeted drugs, and novel antibody-drug conjugate (ADC). Although monoclonal antibodies have produced clinical success, their large molecular weight can limit therapeutic benefits. It is worth noting that in the past 30 years, the FDA has approved small molecule drugs for HER2-positive breast cancers. The lack of effective targets and the occurrence of drug resistance pose significant challenges in the treatment of TNBC. To improve the prognosis of TNBC, it is crucial to search for effective targets and to overcome drug resistance. This review examines the clinical efficacy, adverse effects, resistance mechanisms, and potential solutions of targeted small molecule drugs in both monotherapies and combination therapies. New therapeutic targets, including nuclear export protein 1 (XPO1) and hedgehog (Hh), are emerging as potential options for researchers and become integrated into clinical trials for TNBC. Additionally, there is growing interest in the potential of targeted protein degradation chimeras (PROTACs), degraders of rogue proteins, as a future therapy direction. This review provides potentially valuable insights with clinical implications.

Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)—a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.

In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications. The successful cases provide valuable information for optimizing efficacy and enhancing pharmacokinetic properties through strategies like macrocyclization, bioequivalent group utilization, prodrug synthesis, and conformation restriction. Therefore, gaining an in-depth understanding of the design principles and strategies underlying these drugs will greatly facilitate the development of new therapeutic agents. This review focuses on the research and development process of these newly approved small molecule drugs including drug design, structural modification, and improvement of pharmacokinetic properties to inspire future research in this field. [Display omitted] • The clinical applications and mechanisms of action of newly approved drugs were summarized. • The development processes and design concepts of new drugs were reviewed. • The X-ray crystal structures and molecular binding models of new drugs were exhibited. • The practical structure-activity relationship of each new drugs was summarized. [ABSTRACT FROM AUTHOR]

In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities. Although the biologics license applications including antibody and enzyme replacement therapy set a historical record, the new molecular entities comprising small molecule drugs, diagnostic agent, RNA interference therapy and biomacromolecular peptide still account for over 50 % of the newly approved medications. The novel and privileged scaffolds derived from drugs, active molecules and natural products are consistently associated with the discovery of new mechanisms, the expansion of clinical indications and the reduction of side effects. Moreover, the structural modifications based on the promising scaffolds can provide the clinical candidates with the improved biological activities, bypass the patent protection and greatly shorten the period of new drug discovery. Therefore, conducting an appraisal of drug approval experience and related information will expedite the identification of more potent drug molecules. In this review, we comprehensively summarized the pertinent information encompassing the clinical application, mechanism, elegant design and development processes of 28 small molecule drugs, and expected to provide the promising structural basis and design inspiration for pharmaceutical chemists. [Display omitted] • 55 New drugs including 38 new molecular entities and 17 biologics were approved by the FDA during 2023. • The design strategies, mechanisms and clinical applications of 28 small-molecule drugs were summarized. • The privileged scaffolds and molecular docking were presented to provide the guidance for structural modifications. [ABSTRACT FROM AUTHOR]

Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration., Competing Interests: No potential conflicts of interest are disclosed., (Copyright: © 2024, The Authors.)

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis. The number of cases increased by 2.26 million in 2020, making it the most commonly diagnosed cancer type in the world. TNBCs lack hormone receptor (HR) and human epidermal growth factor 2 (HER2), which limits treatment options. Currently, paclitaxel-based drugs combined with other chemotherapeutics remain the main treatment for TNBC. There is currently no consensus on the best therapeutic regimen for TNBC. However, there have been successful clinical trials exploring large-molecule monoclonal antibodies, small-molecule targeted drugs, and novel antibody-drug conjugate (ADC). Although monoclonal antibodies have produced clinical success, their large molecular weight can limit therapeutic benefits. It is worth noting that in the past 30 years, the FDA has approved small molecule drugs for HER2-positive breast cancers. The lack of effective targets and the occurrence of drug resistance pose significant challenges in the treatment of TNBC. To improve the prognosis of TNBC, it is crucial to search for effective targets and to overcome drug resistance. This review examines the clinical efficacy, adverse effects, resistance mechanisms, and potential solutions of targeted small molecule drugs in both monotherapies and combination therapies. New therapeutic targets, including nuclear export protein 1 (XPO1) and hedgehog (Hh), are emerging as potential options for researchers and become integrated into clinical trials for TNBC. Additionally, there is growing interest in the potential of targeted protein degradation chimeras (PROTACs), degraders of rogue proteins, as a future therapy direction. This review provides potentially valuable insights with clinical implications., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2024. Published by Elsevier Inc.)

A series of benzothiazoles were designed and synthesized as novel PCSK9 inhibitors [Display omitted] Proprotein convertase subtilisin kexin type 9 (PCSK9) is a clinically validated target on the treatment of cardiovascular disease (CVD). PCSK9 can regulate the hepatocyte surface low density lipoprotein receptor (LDLR) level by binding to LDLR and leading to their degradation in the lysosome. The clinical use of two monoclonal antibodies (alirocumab and evolocumab, approved in 2015) and one small interfering RNA (inclisiran, approved in 2020) which can inhibit PCSK9 function proved that they are very effective in lowering low density lipoprotein cholesterol (LDL-C). However, the high treatment costs and parenteral administration of these drugs prohibited widespread use and reduced their long-term advantage. Comparatively, small molecule drugs have many incomparable advantages of macromolecules, such as lower treatment cost, more drug administration options, superior pharmacokinetic properties, less adverse immunogenic responses and better affordable production. In this paper, we identified a series of benzothiazoles small molecule PCSK9 inhibitors through extensive screening. The structure and activity relationship (SAR) was summarized to facilitate further optimization. Moreover, the primary mechanism of action of the most potent compound was also investigated. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia among middle-aged and elderly individuals. Accelerating the prevention and treatment of AD has become an urgent problem. New technology including Computer-aided drug design (CADD) can effectively reduce the medication cost for patients with AD, reduce the cost of living, and improve the quality of life of patients, providing new ideas for treating AD. This paper reviews the pathogenesis of AD, the latest developments in CADD and other small-molecule docking technologies for drug discovery and development; the current research status of small-molecule compounds for AD at home and abroad from the perspective of drug action targets; the future of AD drug development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

There shall probably be no "magic bullet" for Alzheimer's; rather, we should be pursuing a "magic shotgun blast" that will target multiple complementary therapeutic receptors. Although protein misfolding/oligomerization will probably be one of these targets, this alone is insufficient and will require the co-administration of other therapeutic entities engaging targets, such as immunopathy, gliopathy, mitochondriopathy, synaptotoxicity or others. Although polypharmacy is emerging as the preferred therapeutic route, many questions remain unanswered. Should this be a cocktail of biologics, a concoction of small molecules, or a judicious combination of both? Biologics and small molecule drugs display both strengths and weaknesses. When addressing a disease as complex and globally important as Alzheimer's, there should be room for the continuing development of both of these therapeutic classes. Each has much to offer, and when used with their advantages and disadvantages in clear focus, an ultimate solution will probably require contributions from both., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)