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p. falciparum

Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

August 17, 2020 - 13:13 -- Open Access
Author(s): 
Mahindra A, Janha O, Mapesa K, Sanchez-Azqueta A, Alam MM, Amambua-Ngwa A, Nwakanma DC, Tobin AB, Jamieson AG
Reference: 
J Med Chem. 2020 Aug 11

The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we describe the synthesis of our initial hit TCMDC-135051 (1) and efforts to establish a structure-activity relationship with a 7-azaindole-based series.

Prevalence of severe Plasmodium knowlesi infection and risk factors related to severe complications compared with non-severe P. knowlesi and severe P. falciparum malaria: a systematic review and meta-analysis

July 30, 2020 - 14:07 -- Open Access
Author(s): 
Kotepui M, Kotepui KU, Milanez GD, Masangkay FR
Reference: 
Infect Dis Poverty. 2020 Jul 29; 9(1):106

Plasmodium knowlesi is a potential cause of severe and fatal malaria, but comprehensive studies of its pooled prevalence and risk factors are lacking. This study aimed to explore the prevalence and risk factors related to severe P. knowlesi infection.

Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity

July 21, 2020 - 12:14 -- Open Access
Author(s): 
Vanaerschot M, Murithi JM, Fidock DA, et al.
Reference: 
Cell Chem Biol. 2020 Jul 16; 27(7):806-816.e8

The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation.

NOT Open Access | A Chemically Stable Fluorescent Mimic of Dihydroartemisinin, Artemether, and Arteether with Conserved Bioactivity and Specificity Shows High Pharmacological Relevance to the Antimalarial Drugs

July 20, 2020 - 14:52 -- NOT Open Access
Author(s): 
Sissoko A, Vásquez-Ocmín P, Duval R, et al.
Reference: 
ACS Infect Dis. 2020 Jul 10; 6(7):1532-1547

Three novel tracers designed as fluorescent surrogates of artemisinin-derived antimalarial drugs (i.e., dihydroartemisinin, artemether, arteether, and artemisone) were synthesized from dihydroartemisinin.

Plasmodium spp. mixed infection leading to severe malaria: a systematic review and meta-analysis

July 8, 2020 - 15:36 -- Open Access
Author(s): 
Kotepui M, Kotepui KU, De Jesus Milanez G, Masangkay FR
Reference: 
Sci Rep. 2020 Jul 6;10(1):11068

Mixed Plasmodium malaria infections can lead to severe malaria. This systematic review and meta-analysis aimed to explore the prevalence of severe mixed Plasmodium malaria infection and to compare it with the prevalence of severe P. falciparum malaria mono-infection across the included studies. Original English-language research articles from PubMed, Scopus, and ISI Web of Science were identified and screened.

NOT Open Access | Computational chemogenomics drug repositioning strategy enables the discovery of Epirubicin as a new repurposed hit for P. falciparum and P. vivax

June 30, 2020 - 14:57 -- NOT Open Access
Author(s): 
Ferreira LT, Rodrigues J, Costa FTM, et al.
Reference: 
Antimicrob Agents Chemother. 2020 Jun 29:AAC.02041-19

Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks and time-to-market. Herein we have used this strategy to identify novel antimalarial hits. We performed a comparative in silico chemogenomics approach to select Plasmodium falciparum and P. vivax proteins as potential drug targets and analyzed these using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation.

Comparison of real time and malachite-green based loop-mediated isothermal amplification assays for the detection of Plasmodium vivax and P. falciparum

June 15, 2020 - 15:10 -- Open Access
Author(s): 
Barazorda KA, Salas CJ, Bishop DK, Lucchi N, Valdivia HO
Reference: 
PLoS ONE 15(6): e0234263

The current context of malaria elimination requires urgent development and implementation of highly sensitive and specific methods for prompt detection and treatment of malaria parasites. Such methods should overcome current delays in diagnosis, allow the detection of low-density infections and address the difficulties in accessing remote endemic communities. In this study, we assessed the performance of the RealAmp and malachite-green loop mediated isothermal amplification (MG-LAMP) methodologies, using microscopy and conventional nested-PCR as reference techniques.

Not Open Access | Plastid biogenesis in malaria parasites requires the interactions and catalytic activity of the Clp proteolytic system

June 2, 2020 - 14:02 -- NOT Open Access
Author(s): 
Florentin A, Stephens DR, Brooks CF, Baptista RP, Muralidharan V
Reference: 
Proc Natl Acad Sci U S A. 2020 Jun 1:201919501

The human malaria parasite, Plasmodium falciparum, contains an essential plastid called the apicoplast. Most apicoplast proteins are encoded by the nuclear genome and it is unclear how the plastid proteome is regulated. Here, we study an apicoplast-localized caseinolytic-protease (Clp) system and how it regulates organelle proteostasis. Using null and conditional mutants, we demonstrate that the P. falciparum Clp protease (PfClpP) has robust enzymatic activity that is essential for apicoplast biogenesis.

Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like CDPK1, a multistage growth regulator of P. falciparum

May 14, 2020 - 12:21 -- Open Access
Author(s): 
Jain R, Gupta S, Munde M, Pati S, Singh S
Reference: 
Biochem J. 2020 May 13. pii: BCJ20200045

Upon Plasmodium falciparum merozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub of intra-erythrocytic proliferative stages of parasite. Given its high abundance and multidimensional attributes in parasite life-cycle, this is a lucrative target for desiging antimalarials.

Unsymmetrical Bisquinolines with High Potency against P. falciparum Malaria

May 14, 2020 - 12:18 -- Open Access
Author(s): 
Liebman KM, Burgess SJ, Gunsaru B, Kelly JX, Li Y, Morrill W, Liebman MC, Peyton DH
Reference: 
Molecules. 2020 May 10;25(9). pii: E2251

Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered.

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