Breaking the unvirtuous cycle: barriers and opportunities for research and development in Paraguay. A case study.

Introduction: Medical research and development (R&D) is an undoubtedly relevant activity to drive innovation, improve healthcare policies and bring patients treatment opportunities for common and rare diseases. Equity and inclusion are matters of concern in research. High-income countries' research teams are more likely to have more impactful publications, grant funding, and clinical trials than middle or low-income countries. Low budget allocations to R&D and existing gaps in regulatory frameworks are some obstacles to growth. This unvirtuous cycle results in scarce advances in common endemic diseases and the underrepresentation of specific populations in innovative therapeutics research. Materials and methods: We conducted a policy review and qualitative research to determine the principal characteristics of basic and clinical medical research in Paraguay, as well as barriers and facilitators to improve innovative R&D strategies in this country. To this aim, we examined published articles from 2005 to 2020, the organizational structure of national research agencies, the current regulation framework, and the composition and experience of local research groups and ethical review boards (ERBs). In addition, we performed semi-structured interviews to evaluate perceptions and expectations from different stakeholders, including investigators, ERBs members, sponsor associates, and Regulatory Agency executive staff. Results: In 2018, Paraguay ranked 10th out of 12 South American countries in total number of publications and cumulative h-index score. Total Gross Domestic Product (GDP) allocation for R&D was 0.15%, ranking eighth out of 12 in the region. In 2021, the number of trials registered on ClinicalTrials.gov was 52, with only 16 ongoing recruiting studies at that time.Some of the main barriers identified included low incentives for academic careers and lack of experience in pharmaceutical research. An emergent necessity to develop a straight- forward normative framework was detected. Main facilitators included the development of two research initiative programs (PRONII and PROCIENCIA) from CONACYT (National Council of Science and Technology) which were associated with higher budget allocation and total number of publications in the 2011 to 2017 period. A total of six stakeholders participated in the semi-structured surveys. Interviewees highlighted the necessity of a centralized policy to promote R&D, which incorporates investigators and ERBs training, the development of standardized procedures, and the dissemination of research activities. Sponsor associates underlined that real-world evidence may represent a distinctive opportunity to enhance local research. Conclusion: Coordinated efforts are needed to break the unvirtuous cycle. There is an increasing interest in enhancing health research in Paraguay, materialized in the creation of specific programs that encourage the collaborative work of healthcare providers, basic scientists, and private investors. Nonetheless, a comprehensive approach is needed also to strengthen regulatory agencies and attract external sponsorship. While modern and currently popular topics, including artificial intelligence, real-world data, and translational research may represent key opportunities to seek investment, special policies should be adopted to prioritize research on the determinants of health in the Paraguayan population.

Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells.

Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.

The effects of dendritic cell-based vaccines in the tumor microenvironment: Impact on myeloid-derived suppressor cells.

Dendritic cells (DCs) are a heterogenous population of professional antigen presenting cells whose main role is diminished in a variety of malignancies, including cancer, leading to ineffective immune responses. Those mechanisms are inhibited due to the immunosuppressive conditions found in the tumor microenvironment (TME), where myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells known to play a key role in tumor immunoevasion by inhibiting T-cell responses, are extremely accumulated. In addition, it has been demonstrated that MDSCs not only suppress DC functions, but also their maturation and development within the myeloid linage. Considering that an increased number of DCs as well as the improvement in their functions boost antitumor immunity, DC-based vaccines were developed two decades ago, and promising results have been obtained throughout these years. Therefore, the remodeling of the TME promoted by DC vaccination has also been explored. Here, we aim to review the effectiveness of different DCs-based vaccines in murine models and cancer patients, either alone or synergistically combined with other treatments, being especially focused on their effect on the MDSC population.

Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target.

The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi Hence, our data establish PfCLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.

A high throughput screen for next-generation leads targeting malaria parasite transmission.

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2-1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male-female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold.

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.

Design, synthesis and antimalarial evaluation of novel thiazole derivatives.

As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.

An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS.

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.