A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

The gametocyte pLDH assay is fast, easy to perform, cheap and reproducible and is suitable for screening novel transmission-blocking compounds, which does not require parasite transgenic lines.

In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.

The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite has the potential to severely compromise malaria control. Therefore, the development of new artemisinins in combination with new drugs that impart activities toward both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular, those of resistant parasites, is urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives toward the asexual and gametocyte stages of parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes, in the low-nanomolar range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displayed notable synergism. These data suggest that modulation of redox homeostasis is likely an important druggable process, particularly in gametocytes, and this finding thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.

SARS-CoV-2 symptoms are non-specific and can range from asymptomatic presentation to severe pneumonia. Asymptomatic subjects carrying SARS-CoV-2 often remain undiagnosed and it is still debated whether they develop immunoglobulins (Ig) and how long they persist. The aim of this study was to investigate the development and persistence of antibodies against SARS-CoV-2 in asymptomatic subjects infected by the virus. This follow-up study was performed on the 31 asymptomatic subjects who presented a positive nasal swab or serology against SARS-CoV-2 (Ig against Spike-RBD) in the first part of the UNICORN study (March 2020) aimed at attesting previous or current contacts with the virus in the personnel of the University of Milan. Eight weeks after the first Ig measure, these subjects were invited to donate a second blood sample for testing serum antibodies (IgM, IgG and total antibodies) and to fill-in a structured questionnaire. About 80% of asymptomatic subjects did not present circulating immunoglobulins against SARS-CoV-2 after 8 weeks from a positive nasal swab against the virus. Moreover, in more than 40% of these subjects, no Ig against SARS-CoV-2 were detected at any time. Finally, about two third of subjects with immunoglobulins at baseline did not present IgG against SARS-CoV-2 after 8 weeks. The majority of subjects who developed an asymptomatic SARS-CoV-2 infection do not present antibodies against the RBD-spike protein after 8 weeks of follow-up. These data should be taken into account for the interpretation of the serological evidences on SARS-CoV-2 that are emerging nowadays.

When citing, please refer to the published version. MMP-9 and increases TIMP-1 without affecting TIMP-2 secretion, whereas in human 60 keratinocytes it reduces MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. 61Provided that the phenotype of the cellular environment is better understood, chronic wounds 62 might be targeted by new oxygenating compounds such as chitosan-or dextran-shelled and 63 2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets (OLNs). Here, we investigated 64 the effects of hypoxia and dextran-shelled OLNs on the pro-angiogenic phenotype and 65 behavior of human dermal microvascular endothelium (HMEC-1 cell line), another cell 66 population playing key roles during wound healing. Normoxic HMEC-1 constitutively 67 released MMP-2, TIMP-1 and TIMP-2 proteins, but not MMP-9. Hypoxia enhanced MMP-2 68 and reduced TIMP-1 secretion, without affecting TIMP-2 levels, and compromised cell 69 ability to migrate and invade the extracellular matrix. When taken up by HMEC-1, nontoxic 70OLNs abrogated the effects of hypoxia, restoring normoxic MMP/TIMP levels and 71 promoting cell migration, matrix invasion, and formation of microvessels. These effects were 72 specifically dependent on time-sustained oxygen diffusion from OLN core, since they were 73 not achieved by oxygen-free nanodroplets or oxygen-saturated solution. Collectively, these 74 data provide new information on the effects of hypoxia on dermal endothelium and support 75 the hypothesis that OLNs might be used as effective adjuvant tools to promote chronic wound 76 healing processes. 77 78Keywords: oxygen; nanodroplet; matrix metalloproteinase (MMP); tissue inhibitor of 79 metalloproteinase (TIMP); human microvascular endothelial cell (HMEC); skin. 80 5 Introduction 81 82After injury, skin integrity must be restored promptly to reestablish the homeostatic 83 mechanisms, minimize fluid loss, and prevent infection [Greaves et al., 2013]. This is 84 achieved through wound healing, a complex biological process where multiple pathways are 85 simultaneously activated to induce tissue repair and regeneration. Traditionally, acute wound 86 healing is defined as a complex multi-step and multi-cellular process, distinguished in four 87 phases involving different cell types: i) hemostasis, involving platelets; ii) inflammation, 88 involving neutrophils, monocytes, and macrophages; iii) proliferation, involving 89 keratinocytes, endothelial cells, and fibroblasts; and iv) matrix remodeling, involving 90 keratinocytes, myofibroblasts, and endothelial cells. [Diegelmann et al., 2004]. In particular, 91 during the third and fourth phases, the endothelium plays a pivotal role, since wound 92 microvasculature is rebuilt through angiogenesis to restore the supply of oxygen, blood 93 constituents and nutrients to the regenerating tissue, helping to promote fibroplasia and 94 prevent sustained tissue hypoxia [Eming et al., 2014]. Notably, oxygen represents a key 95 regulator of normal wound healing since it is required for collagen deposition, 96 epith...

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This work indicates that the luciferase and gametocyte LDH assays are interchangeable and that their specific advantages can be exploited to design an HTS pipeline leading to new transmission-blocking compounds. Results from these assays consistently defined a gametocyte chemical susceptibility profile, relevant to the planning of future drug discovery strategies.