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Identification of Plasmodium dipeptidyl aminopeptidase allosteric inhibitors by high throughput screening

January 15, 2020 - 09:27 -- Open Access
Sanchez MI, de Vries LE, Lehmann C, Lee JT, Ang KK, Wilson C, Chen S, Arkin MR, Bogyo M, Deu E
PLoS ONE 14(12): e0226270

Dipeptidyl aminopeptidases (DPAPs) are cysteine proteases that cleave dipeptides from the N-terminus of protein substrates and have been shown to play important roles in many pathologies including parasitic diseases such as malaria, toxoplasmosis and Chagas’s disease. Inhibitors of the mammalian homologue cathepsin C have been used in clinical trials as potential drugs to treat chronic inflammatory disorders, thus proving that these enzymes are druggable.

Can Plasmodium's tricks for enhancing its transmission be turned against the parasite? New hopes for vector control

January 14, 2020 - 12:10 -- Open Access
Emami SN, Hajkazemian M, Mozūraitis R
Pathogens and Global Health, 2020 Jan 7:1-11

Approximately 120 years ago the link between mosquito and the malaria transmission was discovered. However, even today it remains an open question whether the parasite is able to direct the blood-seeking and feeding behavior of its mosquito vector to maximize the probability of transmission. If the parasite has this ability, could it occur only through the alteration of the vertebrate host’s volatile organic compounds (VOCs) and/or the parasite alteration of the behavior of the infected vector in a manner that favors its transmission?

NOT Open Access | Discovery of 6'-chloro-N-methyl-5'-(phenylsulfonamido)-[3,3'-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

January 14, 2020 - 12:02 -- NOT Open Access
Liang X, Jiang Z, Liu Q, et al.
European Journal of Medicinal Chemistry, Volume 188, 15 February 2020, 112012

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase.

NOT Open Access | Plasmodium asexual growth and sexual development in the haematopoietic niche of the host

January 14, 2020 - 09:39 -- NOT Open Access
Venugopal K, Hentzschel F, Valkiūnas G, Marti M
Nature Reviews Microbiology (2020), Jan 9

Plasmodium spp. parasites are the causative agents of malaria in humans and animals, and they are exceptionally diverse in their morphology and life cycles. They grow and develop in a wide range of host environments, both within blood-feeding mosquitoes, their definitive hosts, and in vertebrates, which are intermediate hosts. This diversity is testament to their exceptional adaptability and poses a major challenge for developing effective strategies to reduce the disease burden and transmission. Following one asexual amplification cycle in the liver, parasites reach high burdens by rounds of asexual replication within red blood cells. A few of these blood-stage parasites make a developmental switch into the sexual stage (or gametocyte), which is essential for transmission.

Immunity against sexual stage Plasmodium falciparum and Plasmodium vivax parasites

December 23, 2019 - 14:55 -- Open Access
de Jong RM, Tebeje SK, Meerstein-Kessel L, Tadesse FG, Jore MM, Stone W, Bousema T
Immunol Rev. 2019 Dec 16.

The efficient spread of malaria from infected humans to mosquitoes is a major challenge for malaria elimination initiatives. Gametocytes are the only Plasmodium life stage infectious to mosquitoes. Here, we summarize evidence for naturally acquired anti‐gametocyte immunity and the current state of transmission blocking vaccines (TBV). Although gametocytes are intra‐erythrocytic when present in infected humans, developing Plasmodium falciparum gametocytes may express proteins on the surface of red blood cells that elicit immune responses in naturally exposed individuals.

Tamoxifen activity against Plasmodium in vitro and in mice

December 3, 2019 - 15:24 -- Open Access
Ada Weinstock, Julio Gallego-Delgado, Cláudia Gomes, Julian Sherman, Cyrus Nikain, Sandra Gonzalez, Edward Fisher and Ana Rodriguez
Malaria Journal 2019 18:378, 27 November 2019

Tamoxifen is an oestrogen receptor modulator that is widely used for the treatment of early stage breast cancer and reduction of recurrences. Tamoxifen is also used as a powerful research tool for controlling gene expression in the context of the Cre/loxP site-specific recombination system in conditional mutant mice.

Not Open Access | B cells are sufficient to prime the dominant CD4+ Tfh response to Plasmodium infection

November 30, 2019 - 20:01 -- NOT Open Access
Arroyo EN, Pepper M.
J Exp Med. 2019 Nov 20. pii: jem.20190849.

CD4+ T follicular helper (Tfh) cells dominate the acute response to a blood-stage Plasmodium infection and provide signals to direct B cell differentiation and protective antibody expression. We studied antigen-specific CD4+ Tfh cells responding to Plasmodium infection in order to understand the generation and maintenance of the Tfh response.

Not Open Access | Novel molecular diagnostic technique for detecting the different species of Plasmodium

November 30, 2019 - 15:28 -- NOT Open Access
Sharma S, Kaitholia K, Bharti RS, Singh MP, Mishra N
Infect Genet Evol. 2019 Nov 18:104122.

Early diagnosis and comprehensive treatment are the mainstays of malaria disease control. Polymerase chain reaction (PCR) with 18r RNA as a diagnostic target still has problem in sensitivity.

Not Open Access | Plasmodium comparative genomics

November 26, 2019 - 20:33 -- NOT Open Access
Lisa Ranford-Cartwright, Elena Gómez-Díaz
Briefings in Functional Genomics, Volume 18, Issue 5, September 2019, Pages 267–269

Malaria is a serious infectious disease caused by unicellular eukaryotic parasites of the genus Plasmodium. Today more than 200 species exist [1], and whole-genome sequence data is available for around 22 species 

Cutting back malaria: CRISPR/Cas9 genome editing of Plasmodium

November 26, 2019 - 20:31 -- Open Access
Marcus C S Lee, Scott E Lindner, Jose-Juan Lopez-Rubio, Manuel Llinás
Briefings in Functional Genomics, Volume 18, Issue 5, September 2019, Pages 281–289

CRISPR/Cas9 approaches are revolutionizing our ability to perform functional genomics across a wide range of organisms, including the Plasmodium parasites that cause malaria. The ability to deliver single point mutations, epitope tags and gene deletions at increased speed and scale is enabling our understanding of the biology of these complex parasites, and pointing to potential new therapeutic targets. In this review, we describe some of the biological and technical considerations for designing CRISPR-based experiments, and discuss potential future developments that broaden the applications for CRISPR/Cas9 interrogation of the malaria parasite genome.


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