抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Genetics and analysis of quantitative traits

Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

https://www.cell.com/cell/pdf/S0092-8674(09)01243-4.pdf

Cellular and Molecular Mechanisms of Pain

HHpred is a fast server for remote protein homology detection and structure prediction and is the first to implement pairwise comparison of profile hidden Markov models (HMMs). It allows to search a wide choice of databases, such as the PDB, SCOP, Pfam, SMART, COGs and CDD. It accepts a single query sequence or a multiple alignment as input. Within only a few minutes it returns the search results in a user-friendly format similar to that of PSI-BLAST. Search options include local or global alignment and scoring secondary structure similarity. HHpred can produce pairwise query-template alignments, multiple alignments of the query with a set of templates selected from the search results, as well as 3D structural models that are calculated by the MODELLER software from these alignments. A detailed help facility is available. As a demonstration, we analyze the sequence of SpoVT, a transcriptional regulator from Bacillus subtilis. HHpred can be accessed at http://protevo.eb.tuebingen.mpg.de/hhpred.

/pdf/the-hhpred-interactive-server-for-protein-homology-detection-hwdomzzy1s.pdf

The HHpred interactive server for protein homology detection and structure prediction

Venom peptides are potent and selective modulators of voltage-gated ion channels that regulate neuronal function both in health and in disease. We previously identified the spider venom peptide Tap1a from the Venezuelan tarantula Theraphosa apophysis that targeted multiple voltage-gated sodium and calcium channels in visceral pain pathways and inhibited visceral mechano-sensing neurons contributing to irritable bowel syndrome. In this work, alanine scan and domain activity analysis revealed Tap1a inhibited sodium channels by binding with nanomolar affinity to the voltage-sensor domain II utilising conserved structure-function features characteristic of spider peptides belonging to family NaSpTx1. In order to speed up the development of optimized NaV-targeting peptides with greater inhibitory potency and enhanced in vivo activity, we tested the hypothesis that incorporating residues identified from other optimized NaSpTx1 peptides into Tap1a could also optimize its potency for NaVs. Applying this approach, we designed the optimized peptide Tap1a-OPT exhibiting 18 to 41-fold increased potency for NaV1.1, NaV1.2, NaV1.3, NaV1.6 and NaV1.7 involved in several neurological disorders including acute and chronic pain, motor neuron disease and epilepsy. This enhanced potency arose through a slowed off-rate mechanism. Optimized inhibition of NaV channels observed in vitro translated in vivo, with reversal of nocifensive behaviours in a murine model of NaV-mediated pain also enhanced by Tap1a-OPT compared to Tap1a. Molecular docking studies suggested that improved interactions between the loops 3 and 4, and C-terminal of Tap1a-OPT and the NaV channel voltage-sensor domain II were the main drivers of optimized potency. Overall, the rationally designed peptide Tap1a-OPT displayed new and refined structure-function features which are likely the major contributors to its enhanced therapeutic properties observed in vivo. This work contributes to the rapid engineering and optimization of potent and selective spider peptides multi-targeting NaV channels, and the research into novel drugs to treat neurological diseases.

/pdf/engineering-of-a-spider-peptide-via-conserved-structure-1jbb0iob99.pdf

Engineering of a Spider Peptide via Conserved Structure-Function Traits Optimizes Sodium Channel Inhibition In Vitro and Anti-Nociception In Vivo

Structural mechanisms for alpha-conotoxin activity at the human alpha 3 beta 4 nicotinic acetylcholine receptor.

Lessons and questions from the structure of the Spo0A activation domain: Response

Ion channels are important drug targets for a range of diseases including pain, epilepsy and addiction. However, progress towards the development of more selective inhibitors that generate fewer dose-limiting side effects, or open up new therapeutic opportunities, has been slow. Due to the potentially higher selectivity offered by venom peptides, many pharmaceutical companies are embracing biological-based approaches to the identification of novel ion channel modulators. This will help overcome some of the limitations of low molecular weight modulators, whose affinity is often driven by factors such as lipid solubility and interactions with more conserved transmembrane domains. This chapter will cover this rapidly emerging field, providing examples of venom peptide and small molecule approaches towards the development of Cav2.2, Nav1.7 and Kv1.3 inhibitors for the treatment of pain and autoimmune diseases.

CHAPTER 12:Does Nature do Ion Channel Drug Discovery Better than Us?

Grafting different regions of related peptides together to form a single protein chimera is a valuable tool in rapidly elucidating regions of activity or selectivity in peptides and proteins. To conveniently evaluate the contributions of the N- and C-terminal segments of ω-conotoxins CVID and MVIIC to activity, we employed native chemical ligation in CVID-MVIIC chimera design. Assembly of these peptide segments via the ligation method improved overall yield and coupling efficiency, with no difficult sequences encountered in contrast to the traditional full-length chain assembly of CVID. Radio-ligand binding assays revealed regions of importance for receptor recognition.

Rapid Access to ω-Conotoxin Chimeras using Native Chemical Ligation

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