New targets for antimalarial drug discovery

Guerra, Francisco; Winzeler, Elizabeth A.

doi:10.1016/j.mib.2022.102220

Cited by 3 publications

(3 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Different authors have published reviews on identification of antimalarial targets which could be utilized for antimalarial drug development. − However, the antimalarial discovery landscape has been dynamic in recent years, necessitating an update reflecting the developments toward finding novel antimalarial therapies. Moreover, to the best of our knowledge, there is no review providing a discussion on emerging antimalarial targets with detailed insights into the underlying mechanisms responsible for their biological function.…”

Section: Introductionmentioning

confidence: 99%

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Cheuka,

Njaria,

Mayoka

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors. ■ SIGNIFICANCEFor the first time, we report some emerging antimalarial targets with special emphasis on mechanistic details of how they function. We believe such details are of value in medicinal chemistry toward facilitating rapid design of inhibitors. While considerable efforts have been made regarding drug target identification, the corresponding medicinal chemistry hit identification and hit-to-lead optimization have been insufficient. We believe this Perspective will contribute to bridging the gap between target discovery and inhibitor design.

show abstract

Section: Introductionmentioning

confidence: 99%

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Cheuka,

Njaria,

Mayoka

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…The spread of antimalarial drug resistance has been rapid and extensive (2,3). The limited availability of antimalarials has prompted researchers to develop new treatments (4,5). During its intra-erythrocytic asexual replication, which is exclusively responsible for the clinical symptoms, Plasmodium requires various vitamins as cofactors for biochemical processes (6).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of thiamine analogues with antiplasmodial activity

Fathoni,

Ho,

Chan

et al. 2024

Preprint

View full text Add to dashboard Cite

Thiamine is metabolized into thiamine pyrophosphate (TPP), an essential enzyme cofactor. Previous work has shown that oxythiamine, a thiamine analogue, is metabolized by thiamine pyrophosphokinase (TPK) into oxythiamine pyrophosphate (OxPP) within the malaria parasitePlasmodium falciparum, and then inhibits TPP-dependent enzymes, killing the parasitein vitroandin vivo. To identify a more potent antiplasmodial thiamine analogue, 11 commercially available compounds were tested againstP. falciparumandP. knowlesi. Five active compounds were identified, but only N3-pyridyl thiamine (N3PT), a potent transketolase inhibitor and candidate anticancer lead compound, was found to suppressP. falciparumproliferation with an IC50value 10-fold lower than that of oxythiamine. N3PT was active againstP. knowlesiand was >17 times less toxic to human fibroblast, as compared to oxythiamine. Increasing the extracellular thiamine concentration reduced the antiplasmodial activity of N3PT, consistent with N3PT competing with thiamine/TPP. A transgenicP. falciparumline overexpressing TPK was found to be hypersensitized to N3PT. Docking studies showed an almost identical binding mode in TPK between thiamine and N3PT. Furthermore, we show that [3H]thiamine accumulation, resulting from a combination of transport and metabolism, in isolated parasites is reduced by N3PT. Treatment ofP. berghei-infected mice with 200 mg/kg/day N3PT reduced their parasitemia, prolonged their time to malaria symptoms, and appeared to be non-toxic to mice. Collectively, our studies are consistent with N3PT competing with thiamine for TPK binding and inhibiting parasite proliferation by reducing TPP production, as well as being converted into a TPP antimetabolite that inhibits TPP-dependent enzymes.

show abstract

“…Nonetheless, new antimalarial candidates need to be developed due to the continuous selection of multi-resistant Plasmodium parasites, including the recent emergence of artemisinin-resistant parasites in Africa (Balikagala et al, 2021;Uwimana et al, 2020). Phenotypic screening of chemical libraries against P. falciparum blood-stage parasites cultured in vitro (Gamo et al, 2010) and target-based approaches (recently reviewed in Guerra & Winzeler, 2022) have been used to identify and develop different drug candidates, particularly under the supervision of the Medicines for Malaria Venture (https:// www.mmv.org/). Among the many new drug targets identified, Plasmodium subtilisin-like serine protease 1 (SUB1) has emerged as a promising candidate because it meets several of the expected prerequisites: (i) the sequence and organization of the SUB1 active site are highly related to bacterial subtilisins and are significantly distant from human subtilisins (Barale et al, 1999;Giganti et al, 2014), suggesting that highly specific SUB1 inhibitors could be produced without unwanted off-target effects, (ii) the sub1 gene is required for the Plasmodium life cycle (Yeoh et al, 2007;Thomas et al, 2018), thus excluding biological redundancy, and (iii) SUB1 is a key player in the finely regulated cascade of proteases that govern egress of the parasite from the host red blood cells (Thomas et al, 2018;Yeoh et al, 2007;Pino et al, 2017;Nasamu et al, 2017;Collins et al, 2013;Tan et al, 2021;Mukherjee et al, 2022;Dvorin & Goldberg, 2022), a key step in the asexual intraerythrocytic cycle of Plasmodium sp.…”

Section: Introductionmentioning

confidence: 99%

3D structures of the Plasmodium vivax subtilisin-like drug target SUB1 reveal conformational changes to accommodate a substrate-derived α-ketoamide inhibitor

Martinez,

Batista,

Maurel

et al. 2023

Acta Crystallogr D Struct Biol

View full text Add to dashboard Cite

The constant selection and propagation of multi-resistant Plasmodium sp. parasites require the identification of new antimalarial candidates involved in as-yet untargeted metabolic pathways. Subtilisin-like protease 1 (SUB1) belongs to a new generation of drug targets because it plays a crucial role during egress of the parasite from infected host cells at different stages of its life cycle. SUB1 is characterized by an unusual pro-region that tightly interacts with its cognate catalytic domain, thus precluding 3D structural analysis of enzyme–inhibitor complexes. In the present study, to overcome this limitation, stringent ionic conditions and controlled proteolysis of recombinant full-length P. vivax SUB1 were used to obtain crystals of an active and stable catalytic domain (PvS1Cat) without a pro-region. High-resolution 3D structures of PvS1Cat, alone and in complex with an α-ketoamide substrate-derived inhibitor (MAM-117), showed that, as expected, the catalytic serine of SUB1 formed a covalent bond with the α-keto group of the inhibitor. A network of hydrogen bonds and hydrophobic interactions stabilized the complex, including at the P1′ and P2′ positions of the inhibitor, although P′ residues are usually less important in defining the substrate specificity of subtilisins. Moreover, when associated with a substrate-derived peptidomimetic inhibitor, the catalytic groove of SUB1 underwent significant structural changes, particularly in its S4 pocket. These findings pave the way for future strategies for the design of optimized SUB1-specific inhibitors that may define a novel class of antimalarial candidates.

show abstract

New targets for antimalarial drug discovery

Cited by 3 publications

References 75 publications

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Identification and characterization of thiamine analogues with antiplasmodial activity

3D structures of the Plasmodium vivax subtilisin-like drug target SUB1 reveal conformational changes to accommodate a substrate-derived α-ketoamide inhibitor

Contact Info

Product

Resources

About