Computational Workflow to Design Novel Vaccine Candidates and Small-Molecule Therapeutics for Schistosomiasis.

Human schistosomiasis, caused by the trematode, is a neglected parasitic disease affecting over 250 million people worldwide. There is no vaccine, and the single available drug is threatened by drug resistance. This study presents a computational approach to designing multiepitope vaccines (MEVs) targeting the cercarial (CMEV) and schistosomular (SMEV) stages of schistosomes, and identifies potential schistosomicidal compounds from the Medicine for Malaria Ventures (MMV) and SuperNatural Database (SND) libraries.

Human schistosomiasis in Nigeria: present status, diagnosis, chemotherapy, and herbal medicines.

Schistosomiasis is a neglected tropical disease caused by a parasitic, trematode blood fluke of the genus Schistosoma. With 20 million people infected, mostly due to Schistosoma haematobium, Nigeria has the highest burden of schistosomiasis in the world. We review the status of human schistosomiasis in Nigeria regarding its distribution, prevalence, diagnosis, prevention, orthodox and traditional treatments, as well as snail control strategies.

Discovery of pyrazolopyrrolidinones as potent, broad-spectrum inhibitors of infection.

Introduction: Leishmaniasis is a parasitic disease that affects more than 1 million people worldwide annually, predominantly in resource-limited settings. The challenge in compound development is to exhibit potent activity against the intracellular stage of the parasite (the stage present in the mammalian host) without harming the infected host cells. We have identified a compound series (pyrazolopyrrolidinones) active against the intracellular parasites of and ; the causative agents of visceral and cutaneous leishmaniasis in the Old World, respectively.

Identification of Novel Genes and Proteoforms in through a Proteogenomic Approach.

RNA sequencing (RNA-Seq) and mass-spectrometry-based proteomics data are often integrated in proteogenomic studies to assist in the prediction of eukaryote genome features, such as genes, splicing, single-nucleotide (SNVs), and single-amino-acid variants (SAAVs). Most genomes of parasite nematodes are draft versions that lack transcript- and protein-level information and whose gene annotations rely only on computational predictions. is a roundworm species that causes an intestinal inflammatory disease, known as abdominal angiostrongyliasis (AA).

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M and Papain-like Protease PL of SARS-CoV-2.

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (M) and papain-like protease (PL) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against M of SARS-CoV-2.

Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2.

Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination.

The main protease (M, 3CL) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M inhibitors. Compounds and exhibited excellent SARS-CoV-2 M inhibition with / of 58,700 M s ( = 0.

Identification of Leucinostatins from sp. as Antiparasitic Agents against .

Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite , have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against , are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents.

Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against .

Gallinamide A, a metabolite of the marine cyanobacterium sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated the potency of gallinamide A and 23 synthetic analogues against intracellular amastigotes and the cysteine protease, cruzain.

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2.

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In the present work, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2.

Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L.

Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry.

Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas Disease.

Chagas disease (CD), caused by the parasite Trypanosoma cruzi, is one of nineteen neglected tropical diseases. CD is a vector-borne disease transmitted by triatomines, but CD can also be transmitted through blood transfusions, organ transplants, T. cruzi-contaminated food and drinks, and congenital transmission.

Dysregulation of Glycerophosphocholines in the Cutaneous Lesion Caused by in Experimental Murine Models.

Cutaneous leishmaniasis (CL) is the most common disease form caused by a parasite infection and considered a neglected tropical disease (NTD), affecting 700,000 to 1.2 million new cases per year in the world. is one of several different species of the genus that can cause CL.

Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases.

Chagas disease and Human African Trypanosomiasis (HAT) are caused by Trypanosoma cruzi and T. brucei parasites, respectively. Cruzain (CRZ) and Rhodesain (RhD) are cysteine proteases that share 70% of identity and play vital functions in these parasites.

Keratitis: an update on amebicidal and cysticidal drug screening methodologies and potential treatment with azole drugs.

: encompasses several species of free-living ameba encountered commonly throughout the environment. Unfortunately, these species of ameba can cause opportunistic infections that result in keratitis, granulomatous amebic encephalitis, and occasionally systemic infection.: This review discusses relevant literature found through PubMed and Google scholar published as of January 2021.

A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells.

Host-cell cysteine proteases play an essential role in the processing of the viral spike protein of SARS coronaviruses. K777, an irreversible, covalent inactivator of cysteine proteases that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 viral infectivity in several host cells: Vero E6 (EC< 74 nM), HeLa/ACE2 (4 nM), Caco-2 (EC = 4.3 μM), and A549/ACE2 (<80 nM).

First report on prevalence of SARS-CoV-2 infection among health-care workers in Nicaragua.

The Nicaraguan COVID-19 situation is exceptional for Central America. The government restricts testing and testing supplies, and the true extent of the coronavirus crisis remains unknown. Dozens of deaths have been reported among health-care workers.

An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets.

Potent anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L.

The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target.

A cysteine protease inhibitor blocks SARS-CoV-2 infection of human and monkey cells.

K777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ACE2, Caco-2, A549/ACE2, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ACE2, and 4 nM for HeLa/ACE2 cells.

Long term follow-up of Trypanosoma cruzi infection and Chagas disease manifestations in mice treated with benznidazole or posaconazole.

Chagas' Disease, caused by the protozoan parasite Trypanosoma cruzi, is responsible for up to 41% of the heart failures in endemic areas in South America and is an emerging infection in regions of North America, Europe, and Asia. Treatment is suboptimal due to two factors. First, the lack of an adequate biomarker to predict disease severity and response to therapy; and second, up to 120-days treatment course coupled with a significant incidence of adverse effects from the drug currently used.

Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways.

Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life.

High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for .

Chagas disease, caused by the kinetoplastid parasite , affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA.

Peptidomimetic Vinyl Heterocyclic Inhibitors of Cruzain Effect Antitrypanosomal Activity.

Cruzain, an essential cysteine protease of the parasitic protozoan, , is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (* = 0.