Drug Discovery For Tropical Diseases Research Articles

Unveiling the anti-echinococcal efficacy of amide-based compounds: An in-silico and in-vitro study

Cystic echinococcosis (CE) is a significant global public health concern, particularly in regions where livestock rearing is prevalent. Despite its impact on morbidity and mortality, CE has received insufficient attention compared to other neglected tropical diseases. The complexities in CE management arise from challenges in early detection, effective treatment, and parasite eradication. The present study addresses this gap by exploring innovative therapeutic approaches using amide-based compounds. In recent years, computational approaches and in-vitro studies have become prominent in neglected tropical disease drug discovery. Leveraging insights from previous studies on amide-based compounds with anti-parasitic potential, this study systematically designed, synthesized, and characterized a library of 30 amide compounds. The research integrated in-silico screening, molecular docking, and in-vitro experimentation to assess the anti-echinococcal potential of these compounds. The study identified five promising amide compounds, namely 3,5-dinitro-N-p-tolylbenzamide, N-p-tolyl-1-naphthamide, N-p-tolyl-4-(trifluoromethoxy)benzamide, 4-pentyl-N-p-tolylbenzamide, and 2,3,4,5,6-pentafluoro-N-p-tolylbenzamide, based on their docking scores. These compounds were synthesized and characterized through various spectroscopic techniques, confirming their structural integrity. The in-vitro cytotoxicity assay on HepG2 cell lines revealed varying degrees of cytotoxicity for the synthesized compounds. Notably, 4-pentyl-N-p-tolylbenzamide demonstrated the least cytotoxicity. Subsequent scolicidal activity assessments on E. granulosus protoscoleces demonstrated the potent protoscolicidal activity of N-p-tolyl-1-naphthamide, indicating its potential as an effective anti-echinococcal agent. Overall, this study presents a comprehensive exploration of amide-based compounds as potential therapeutic agents against CE. The findings contribute to the development of innovative strategies for CE treatment, addressing the urgent need for effective and safe drugs in managing this neglected tropical disease.

Use of Artificial Intelligence and Machine Learning for Discovery of Drugs for Neglected Tropical Diseases.

Neglected tropical diseases continue to create high levels of morbidity and mortality in a sizeable fraction of the world’s population, despite ongoing research into new treatments. Some of the most important technological developments that have accelerated drug discovery for diseases of affluent countries have not flowed down to neglected tropical disease drug discovery. Pharmaceutical development business models, cost of developing new drug treatments and subsequent costs to patients, and accessibility of technologies to scientists in most of the affected countries are some of the reasons for this low uptake and slow development relative to that for common diseases in developed countries. Computational methods are starting to make significant inroads into discovery of drugs for neglected tropical diseases due to the increasing availability of large databases that can be used to train ML models, increasing accuracy of these methods, lower entry barrier for researchers, and widespread availability of public domain machine learning codes. Here, the application of artificial intelligence, largely the subset called machine learning, to modelling and prediction of biological activities and discovery of new drugs for neglected tropical diseases is summarized. The pathways for the development of machine learning methods in the short to medium term and the use of other artificial intelligence methods for drug discovery is discussed. The current roadblocks to, and likely impacts of, synergistic new technological developments on the use of ML methods for neglected tropical disease drug discovery in the future are also discussed.

WIPO Re:Search: Catalyzing Public-Private Partnerships to Accelerate Tropical Disease Drug Discovery and Development.

Tropical diseases, including malaria and a group of infections termed neglected tropical diseases (NTDs), pose enormous threats to human health and wellbeing globally. In concert with efforts to broaden access to current treatments, it is also critical to expand research and development (R&D) of new drugs that address therapeutic gaps and concerns associated with existing medications, including emergence of resistance. Limited commercial incentives, particularly compared to products for diseases prevalent in high-income countries, have hindered many pharmaceutical companies from contributing their immense product development know-how and resources to tropical disease R&D. In this article we present WIPO Re:Search, an international initiative co-led by BIO Ventures for Global Health (BVGH) and the World Intellectual Property Organization (WIPO), as an innovative and impactful public-private partnership model that promotes cross-sector intellectual property sharing and R&D to accelerate tropical disease drug discovery and development. Importantly, WIPO Re:Search also drives progress toward the United Nations Sustainable Development Goals (SDGs). Through case studies, we illustrate how WIPO Re:Search empowers high-quality tropical disease drug discovery researchers from academic/non-profit organizations and small companies (including scientists in low- and middle-income countries) to leapfrog their R&D programs by accessing pharmaceutical industry resources that may not otherwise be available to them.

Challenges and recent progress in drug discovery for tropical diseases

Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world’s poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.

The Importance of Collaboration between Industry, Academics, and Nonprofits in Tropical Disease Drug Discovery.

Collaborations between academic, industrial, and nonprofit companies can provide sufficient impetus to propel projects that have little economic return; such projects are prevalent in tropical disease drug discovery. In these collaborations, each partner contributes a unique set of skills and technical expertise which is advantageous to the project as a whole. Highly product-focused processes and specialized expertise sets dominate industry groups. When coupled with the strategic guidance from public-private partnerships and the academic tendency to work on high-risk projects with low financial rewards, a powerful combination results. There are numerous examples throughout the literature about these collaborative efforts to combat a variety of tropical diseases (including leishmaniasis, Chagas disease, African sleeping sickness, and malaria), from all stages of the drug discovery process to the advancement of new drugs into the clinic. However, there is still uncertainty from many academic institutions as to how to establish and engage in these research consortiums. This Viewpoint highlights opportunities, benefits, and suggestions for productive collaborations in this disease space.

Distant peer-tutoring of clinical skills, using tablets with instructional videos and Skype: A pilot study in the UK and Malaysia

opted out of publication. Abstract #: 02ITIS023 Data sharing for neglected tropical disease drug discovery: Creating a framework for reducing redundancy and improving global collaboration M. Pollastri; Northeastern University, Boston, MA/US Program/Project Purpose: Context. With the ever widening interest in drug discovery for neglected tropical diseases, increasing numbers of academic and industrial research teams are performing medicinal chemistry optimization of potential new drug agents. One risk of this expansion is the duplication of effort caused by compartmentalized prosecution of research projects that are unknowingly focused on pursuing highly similar research directions. The root cause of this issue is the common practice of doing drug discovery research with high levels of confidentiality, a “best practice” that is typical in the for-profit pharmaceutical industry, where developing and protecting intellectual property (IP) is paramount. A new way of thinking about sharing and protecting research data for NTDs is needed. Project Period. January 2014-onward (indefinite). Why the program/project is in place. The development of a secure data sharing portal could strongly enhance and accelerate NTD drug discovery efforts worldwide, both by reducing redundancy and by engaging smaller, resource-constricted organizations who are performing drug discovery research. Aim. To establish, populate, and operate a new data sharing portal that supports drug discovery for neglected tropical diseases. Structure/Method/Design: Desired Outcomes. We intend to develop a self-sustaining, collaborative data sharing portal that captures chemical structure and biological screening data and that enables the collaborative and informed progression of NTD drug discovery projects, while balancing researchers’ desire for information protection (confidentiality). Participants: The recruitment of participants in the program has been primarily by word of mouth, utilizing social media platforms, professional scientific networks, research seminars and posters, and an opinion piece published in PLOSNeglected Tropical Diseases (DOI: 10.1371/journal.pntd.000286). Sustainability: Viability will be dictated by: (1) Engagement. We plan to have r portal teleconference meetings to discuss recent deposits and ongoing projects. In addition, we aspire to make available unique research resources for participating members in order to incentivize active participation. (2) Funding: we will seek funding from other organizations (NIH, BMGF) in order to further operate the portal. Outcomes & Evaluation: Successes We have secured $25,000 in funding via crowdfunding and established the database. We have also identified large tranches of data for deposit and shared, and have engaged other academic NTD drug discovery groups Monitoring. None conducted. Going Forward: Ongoing challenges? The primary challenge has been to recruit participants who will deposit data into the portal and agree to deposit new data on an ongoing basis. Are there any unmet goals? No How are/may future program activities change as a result? N/A Funding: The pilot phase of this project has been funded by a crowdfunding campaign ($25,000): Abstract #: 02ITIS024 An assessment of data quality in Haiti’s multi-site electronic medical record system N. Puttkammer, J. Baseman, B. Devine, N. Hyppolite, G. France, J. Honore, A. Matheson, S. Zeliadt, K. Yuhas, K. Sherr, J. Cadet, S. Barnhart; University of Washington, Seattle, WA/US, University of Washington, Seattle, WA/US, International Training and Education Center for Health (I-TECH)–Haiti, Port-au-Prince, Haiti, Ministry of Health and Population (MSPP), Port-au-Prince, Haiti, National Program for Control of Malaria (PNCM), Port-au-Prince, Haiti Background: The World Health Organization has identified health information systems as a “building block” for health systems

Data sharing for neglected tropical disease drug discovery: Creating a framework for reducing redundancy and improving global collaboration

Data sharing for neglected tropical disease drug discovery: Creating a framework for reducing redundancy and improving global collaboration

Finding new collaboration models for enabling neglected tropical disease drug discovery.

Neglected tropical diseases (NTDs) have seen a welcome bolstering of activities focused on discovery of new therapies for these diseases. By and large, NTD drug discovery happens in the nonprofit sector—in academic laboratories and in public–private partnerships—though there has also been a significant and tangible influx of data and research contributions from the for-profit biopharmaceutical industry. Sets of screening data against the parasites that cause Chagas disease and African sleeping sickness have been released to the public via ChemBL (https://www.ebi.ac.uk/chemblntd), Collaborative Drug Discovery (http://www. collaborativedrug.com), and PubChem (https://pubchem.ncbi.nlm.nih.gov), and a fair quantity of these data have been produced by the pharmaceutical industry, many times in collaboration with groups in the nonprofit or academic environment. These initial public releases have begun to enable credible drug discovery for tropical diseases, particularly when taken together with new collaborative opportunities with industry that provide access to state-of-theart drug discovery and development capabilities. These facilities include the Tres Cantos Open Lab initiative [1], therapeutics development resources at the National Institute of Allergy and Infectious Diseases [2], and compound screening sets now made available for testing against other pathogens, such as the Malaria Box [3]. Thus, perhaps there has never been a better time to be performing hit-to-lead and lead optimization drug discovery for NTDs.

Opening Lecture] - Natural products and drug discovery for tropical diseases - successes, failures and lessons learned

Opening Lecture] - Natural products and drug discovery for tropical diseases - successes, failures and lessons learned

Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness

Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei . We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.

Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.

Structure-Based Drug Discovery for Tropical Diseases

Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of promising hits and the generation of high quality lead compounds for tropical diseases. This review presents the current progresses and applications of structure-based drug design (SBDD) for the discovery of innovative chemotherapy agents for a variety of parasitic diseases, highlighting the challenges, limitations, and future perspectives in medicinal chemistry.

Scientists and Their Pursuit of Excellence: Crossroads and Gateways (or Who is Who in the Festschrift)

Scientists and Their Pursuit of Excellence: Crossroads and Gateways (or Who is Who in the Festschrift)