Vol 31, No 16 (2024)
- Year: 2024
- Articles: 7
- URL: https://j-morphology.com/0929-8673/issue/view/10020
Anti-Infectives and Infectious Diseases
Targeting Cysteine and Serine Proteases to Discover New Drugs Against Neglected Tropical Diseases
2133-2134
Targeting Cysteine Proteases and their Inhibitors to Combat Trypanosomiasis
Abstract
Background:Trypanosomiasis, caused by protozoan parasites of the Trypanosoma genus, remains a significant health burden in several regions of the world. Cysteine proteases play a crucial role in the pathogenesis of Trypanosoma parasites and have emerged as potential therapeutic targets for the development of novel antiparasitic drugs.
Introduction:This review article aims to provide a comprehensive overview of the role of cysteine proteases in trypanosomiasis and their potential as therapeutic targets. We discuss the biological significance of cysteine proteases in Trypanosoma parasites and their involvement in essential processes, such as host immune evasion, cell invasion, and nutrient acquisition.
Methods:A comprehensive literature search was conducted to identify relevant studies and research articles on the role of cysteine proteases and their inhibitors in trypanosomiasis. The selected studies were critically analyzed to extract key findings and provide a comprehensive overview of the topic.
Results:Cysteine proteases, such as cruzipain, TbCatB and TbCatL, have been identified as promising therapeutic targets due to their essential roles in Trypanosoma pathogenesis. Several small molecule inhibitors and peptidomimetics have been developed to target these proteases and have shown promising activity in preclinical studies.
Conclusion:Targeting cysteine proteases and their inhibitors holds great potential for the development of novel antiparasitic drugs against trypanosomiasis. The identification of potent and selective cysteine protease inhibitors could significantly contribute to the combat against trypanosomiasis and improve the prospects for the treatment of this neglected tropical disease.
2135-2169
Drug Discovery Efforts to Identify Novel Treatments for Neglected Tropical Diseases - Cysteine Protease Inhibitors
Abstract
Background:Neglected tropical diseases are a severe burden for mankind, affecting an increasing number of people around the globe. Many of those diseases are caused by protozoan parasites in which cysteine proteases play a key role in the parasites pathogenesis.
Objective:In this review article, we summarize the drug discovery efforts of the research community from 2017 - 2022 with a special focus on the optimization of small molecule cysteine protease inhibitors in terms of selectivity profiles or drug-like properties as well as in vivo studies. The cysteine proteases evaluated by this methodology include Cathepsin B1 from Schistosoma mansoni, papain, cruzain, falcipain, and rhodesain.
Methods:Exhaustive literature searches were performed using the keywords "Cysteine Proteases" and "Neglected Tropical Diseases" including the years 2017 - 2022. Overall, approximately 3000 scientific papers were retrieved, which were filtered using specific keywords enabling the focus on drug discovery efforts.
Results and Conclusion:Potent and selective cysteine protease inhibitors to treat neglected tropical diseases were identified, which progressed to pharmacokinetic and in vivo efficacy studies. As far as the authors are aware of, none of those inhibitors reached the stage of active clinical development. Either the inhibitors potency or pharmacokinetic properties or safety profile or a combination thereof prevented further development of the compounds. More efforts with particular emphasis on optimizing pharmacokinetic and safety properties are needed, potentially by collaborations of academic and industrial research groups with complementary expertise. Furthermore, new warheads reacting with the catalytic cysteine should be exploited to advance the research field in order to make a meaningful impact on society.
2170-2194
Development in the Inhibition of Dengue Proteases as Drug Targets
Abstract
Background:Viral infections continue to increase morbidity and mortality severely. The flavivirus genus has fifty different species, including the dengue, Zika, and West Nile viruses that can infect 40% of individuals globally, who reside in at least a hundred different countries. Dengue, one of the oldest and most dangerous human infections, was initially documented by the Chinese Medical Encyclopedia in the Jin period. It was referred to as \"water poison,\" connected to flying insects, i.e., Aedes aegypti and Ae-des albopictus. DENV causes some medical expressions like dengue hemorrhagic fever, acute febrile illness, and dengue shock syndrome.
Objective:According to the World Health Organization report of 2012, 2500 million people are in danger of contracting dengue fever worldwide. According to a recent study, 96 million of the 390 million dengue infections yearly show some clinical or subclinical se-verity. There is no antiviral drug or vaccine to treat this severe infection. It can be con-trolled by getting enough rest, drinking plenty of water, and using painkillers. The first dengue vaccine created by Sanofi, called Dengvaxia, was previously approved by the US-FDA in 2019. All four serotypes of the DENV1-4 have shown re-infection in vaccine recipients. However, the usage of Dengvaxia has been constrained by its adverse effects.
Conclusion:Different classes of compounds have been reported against DENV, such as nitrogen-containing heterocycles (i.e., imidazole, pyridine, triazoles quinazolines, quinoline, and indole), oxygen-containing heterocycles (i.e., coumarins), and some are mixed heterocyclic compounds of S, N (thiazole, benzothiazine, and thiazolidinediones), and N, O (i.e., oxadiazole). There have been reports of computationally designed compounds to impede the molecular functions of specific structural and non-structural proteins as potential therapeutic targets. This review summarized the current progress in developing dengue protease inhibitors.
2195-2233
Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?
Abstract
Malaria is a devastating infectious disease that affects large swathes of human populations across the planets tropical regions. It is caused by parasites of the genus Plasmodium, with Plasmodium falciparum being responsible for the most lethal form of the disease. During the intraerythrocytic stage in the human hosts, malaria parasites multiply and degrade hemoglobin (Hb) using a battery of proteases, which include two cysteine proteases, falcipains 2 and 3 (FP-2 and FP-3). Due to their role as major hemoglobinases, FP-2 and FP-3 have been targeted in studies aiming to discover new antimalarials and numerous inhibitors with activity against these enzymes, and parasites in culture have been identified. Nonetheless, cross-inhibition of human cysteine cathepsins remains a serious hurdle to overcome for these compounds to be used clinically. In this article, we have reviewed key functional and structural properties of FP-2/3 and described different compound series reported as inhibitors of these proteases during decades of active research in the field. Special attention is also paid to the wide range of computer-aided drug design (CADD) techniques successfully applied to discover new active compounds. Finally, we provide guidelines that, in our understanding, will help advance the rational discovery of new FP-2/3 inhibitors.
2234-2263
Targeting SmCB1: Perspectives and Insights to Design Antischistosomal Drugs
Abstract
Neglected tropical diseases (NTDs) are prevalent in tropical and subtropical countries, and schistosomiasis is among the most relevant diseases worldwide. In addition, one of the two biggest problems in developing drugs against this disease is related to drug resistance, which promotes the demand to develop new drug candidates for this purpose. Thus, one of the drug targets most explored, Schistosoma mansoni Cathepsin B1 (SmCB1 or Sm31), provides new opportunities in drug development due to its essential functions for the parasite's survival. In this way, here, the latest developments in drug design studies targeting SmCB1 were approached, focusing on the most promising analogs of nitrile, vinyl sulphones, and peptidomimetics. Thus, it was shown that despite being a disease known since ancient times, it remains prevalent throughout the world, with high mortality rates. The therapeutic arsenal of antischistosomal drugs (ASD) consists only of praziquantel, which is widely used for this purpose and has several advantages, such as efficacy and safety. However, it has limitations, such as the impossibility of acting on the immature worm and exploring new targets to overcome these limitations. SmCB1 shows its potential as a cysteine protease with a catalytic triad consisting of Cys100, His270, and Asn290. Thus, design studies of new inhibitors focus on their catalytic mechanism for designing new analogs. In fact, nitrile and sulfonamide analogs show the most significant potential in drug development, showing that these chemical groups can be better exploited in drug discovery against schistosomiasis. We hope this manuscript guides the authors in searching for promising new antischistosomal drugs.
2264-2284
Discovery of Novel Inhibitors of Cruzain Cysteine Protease of Trypanosoma cruzi
Abstract
Chagas disease (CD) is a parasitic disease endemic in several developing coun-tries. According to the World Health Organization, approximately 6-8 million people worldwide are inflicted by CD. The scarcity of new drugs, mainly for the chronic phase, is the main reason for treatment limitation in CD. Therefore, there is an urgent need to dis-cover new targets for which new therapeutical agents could be developed. Cruzain cyste-ine protease (CCP) is a promising alternative because this enzyme exhibits pleiotropic ef-fects by acting as a virulence factor, modulating host immune cells, and interacting with host cells. This systematic review was conducted to discover new compounds that act as cruzain inhibitors, and their effects in vitro were studied through enzymatic assays and molecular docking. Additionally, the advances and perspectives of these inhibitors are discussed. These findings are expected to contribute to medicinal chemistry in view of the design of new, safe, and efficacious inhibitors against Trypanosoma cruzi CCP detected in the last decade (2013-2022) to provide scaffolds for further optimization, aiming toward the discovery of new drugs.
2285-2308