Macrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges

Macrocyclic α-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled α-helical peptide to enter into clinical trials. The principal design concept of stapled α-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an α-helical interface. However, it was the proclivity of such stapled α-helical peptides to exhibit cell permeability and proteolytic stability that underscored their promise as unique macrocyclic peptide drugs for intracellular targets. This perspective highlights key learnings as well as challenges in basic research with respect to structure-based design, innovative chemistry, cell permeability and proteolytic stability that are essential to fulfill the promise of stapled α-helical peptide drug development.     

An increased autophagic flux contributes to the anti-inflammatory potential of urolithin A in macrophages

Background

An extract of Phyllanthus muellerianus and its constituent geraniin have been reported to exert anti-inflammatory activity in vivo. However, orally consumed geraniin, an ellagitannin, shows low bioavailability and undergoes metabolization to urolithins by gut microbiota. This study aimed at comparing geraniin and urolithin A with respect to inhibition of M1 (LPS) polarization of murine J774.1 macrophages and shedding more light on possible underlying mechanisms.

Achieving global mortality reduction targets and universal health coverage: The impact of COVID-19

Wenhui Mao and coauthors discuss possible implications of the COVID-19 pandemic for health aspirations in low- and middle-income countries.

Summary points

• The Coronavirus Disease 2019 (COVID-19) pandemic threatens progress toward a “grand convergence” in global health—universal reduction in deaths from infections and maternal and child health conditions to low levels—and toward achieving universal health coverage (UHC).
• Our analysis suggests that COVID-19 will exacerbate the difficulty of achieving grand convergence targets for tuberculosis (TB), maternal mortality, and, probably, for under-5 mortality. HIV targets are likely to be met.
• By 2035, our analysis suggests that the public sectors of low-income countries (LICs) would only be able to finance about a third of the costs of a package of 120 essential non-COVID-19 health interventions through domestic sources, unless the country increases significantly the priority assigned to the health sector; lower middle-income countries (LMICs) would likewise only be able to finance a little less than half.
• The likelihood of getting back on track for reaching grand convergence and UHC will depend on (i) how quickly COVID-19 vaccines can be deployed in LICs and LMICs; (ii) how much additional public sector health financing can be mobilized from external and domestic sources; and (iii) whether countries can rapidly strengthen and focus their health delivery systems.

     

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures.     

Individual performance in relation to cytonuclear discordance in a northern contact zone between long‐toed salamander (Ambystoma macrodactylum) lineages

Cytonuclear discordance in contact zones between related lineages is common, with mitochondrial clines often being displaced from clines in nuclear allele frequency. Proposed explanations for such a pattern include adaptive introgression of mtDNA or a neutral wake of mtDNA being left behind following hybrid zone movement. However, studies investigating these hypotheses are rare. Our previous survey of genetic variation in the long‐toed salamander (Ambystoma macrodactylum) highlighted a potential case of cytonuclear discordance between two lineages in western Canada. Here, we use additional markers and samples to clarify the extent of this discordance. We simultaneously assess the feeding performance of individuals in a common environment to test for an association between mitotype and individual performance. The genetic results confirm a general pattern of cytonuclear discordance in the focal region. However, we also observed more limited introgression of a diagnostic nuclear marker. Intriguingly, although there were differences in individual performance associated with the transition between mitotypes, these differences were not fully explained by mitotype. Instead, the lowest performance was observed in individuals demonstrating the greatest mismatch between mtDNA and all nuclear markers, suggesting the potential for cytonuclear incompatibilities to be acting. These results highlight the complexity of understanding the causes and consequences of mtDNA introgression and cytonuclear discordance in contact zones.     

Design,Synthesis of Novel Lipids as Chemical Permeation Enhancers and Development of Nanoparticle System for Transdermal Drug Delivery

In the present study, we designed and developed novel lipids that include (Z)-1-(Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z)-octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, ß-estradiol, caffeine, α-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, ß-estradiol, caffeine, α-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150–200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 μm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 μm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP.