Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining.

The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions.

Synthesis and Structure-Activity Relationship of Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease with Antiviral Potency.

The papain-like protease (PLpro) is a highly conserved domain encoded by the coronavirus (CoV) genome and it plays an essential role in the replication and maturation of the virus in addition to weakening host immune response. Due to the virus's reliance on PLpro for survival and propagation, small-molecule inhibitors of PLpro serve as an attractive model for direct-acting antiviral therapeutic agents against SARS-CoV-2. Building upon existing work aimed at designing covalent inhibitors against PLpro, we report the synthesis and structure-activity relationship of analogs based on the known covalent inhibitor 1 (Sanders, et al.

An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry.

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention.

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

High Throughput Repurposing Screen Reveals Compounds with Activity Against Bradyzoites.

causes widespread chronic infections that are not cured by current treatments due to inability to affect semi-dormant bradyzoite stages within tissue cysts. To identify compounds to eliminate chronic infection, we developed a HTS using a recently characterized strain of that undergoes efficient conversion to bradyzoites in intro. Stage-specific expression of luciferase was used to selectively monitor growth inhibition of bradyzoites by the Library of Pharmacological Active Compounds, consisting of 1,280 drug-like compounds.

A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy.

Protein target similarity is positive predictor of in vitro antipathogenic activity: a drug repurposing strategy for Plasmodium falciparum.

Drug discovery is an intricate and costly process. Repurposing existing drugs and active compounds offers a viable pathway to develop new therapies for various diseases. By leveraging publicly available biomedical information, it is possible to predict compounds' activity and identify their potential targets across diverse organisms.

Cryptosporidium life cycle small molecule probing implicates translational repression and an Apetala 2 transcription factor in macrogamont differentiation.

The apicomplexan parasite Cryptosporidium is a leading cause of childhood diarrhea in developing countries. Current treatment options are inadequate and multiple preclinical compounds are being actively pursued as potential drugs for cryptosporidiosis. Unlike most apicomplexans, Cryptosporidium spp.

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (M, 3CL) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CL inhibitor, , bearing an unprecedented trifluoromethoxymethyl ketone warhead.

Synthesis and structure-activity relationships of aryl fluorosulfate-based inhibitors as novel antitubercular agents.

To identify new compounds that can effectively inhibit Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), we screened, synthesized, and evaluated a series of novel aryl fluorosulfate derivatives for their in vitro inhibitory activity against Mtb. Compound 21b exhibited an in vitro minimum inhibitory concentration (MIC) of 0.06 µM against Mtb, no cytotoxicity against both HEK293T and HepG2 mammalian cell lines, and had good in vivo mouse plasma exposure and lung concentration with a 20 mg/kg oral dose, which supports advanced development as a new chemical entity for TB treatment.

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years.

Leishmaniasis is a group of vector-borne, parasitic diseases caused by over 20 species of the protozoan spp. The three major disease classifications, cutaneous, visceral, and mucocutaneous, have a range of clinical manifestations from self-healing skin lesions to hepatosplenomegaly and mucosal membrane damage to fatality. As a neglected tropical disease, leishmaniasis represents a major international health challenge, with nearly 350 million people living at risk of infection a year.

Structure-activity relationship of BMS906024 derivatives for Cryptosporidium parvum growth inhibition.

BMS906024, a γ-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure-activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl β-substituent. However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated.

Adaptive laboratory evolution in S. cerevisiae highlights role of transcription factors in fungal xenobiotic resistance.

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species.

Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3', 5'-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb.

Pharmacokinetics and Pharmacodynamics of Clofazimine for Treatment of Cryptosporidiosis.

Infection with spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed.

Prioritization of Molecular Targets for Antimalarial Drug Discovery.

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery.

The Tuberculosis Drug Accelerator at year 10: what have we learned?

The Tuberculosis Drug Accelerator, an experiment designed to facilitate collaboration in TB drug discovery by breaking down barriers among competing labs and institutions, has reached the 10-year landmark. We review the consortium’s achievements, advantages and limitations and advocate for application of similar models to other diseases.

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions.

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells.