The pH-Low Insertion Peptide (pHLIP) offers the potential to deliver drugs selectively to the cytoplasm of cancer cells based on tumor acidosis. The WT pHLIP inserts into membrane with a pH50 of 6.1 while most solid tumors have extracellular pH (pHe) of 6.5-7.0. To close this gap, a SAR study was carried out to search for pHLIP variants with improved pH-response. We learned that (a) replacing Asp25 with α-aminoadipic acid (Aad) adjusts the pH50 to 6.74, matching average tumor acidity, and (b) replacing Asp14 with γ-carboxyglutamic acid (Gla) increases the sharpness of pH-response (i.e. transition over 0.5 instead of 1 pH unit). These effects are additive — the Asp14Gla/Asp25Aad double variant shows a pH50 of 6.79, with sharper transition than Asp25Aad. Further, the advantage of the double variant over WT pHLIP in terms of cargo delivery was demonstrated in turn-on fluorescence assays and anti-proliferation studies (using paclitaxel as cargo) in A549 lung cancer cells at pH 6.6.

Flavonoids constitute a large family of plant-derived polyphenolic compounds that are found in fruits, vegetables, spices, wines and juices 1. Examples of flavonoids include quercetin, fisetin, luteolin, apeginin, myricetin and many others. Previous studies have shown that these compounds exhibit an array of biological effects that are beneficial to humans, including antiviral, antioxidative, anti-inflammatory and anticarcinogenic. The solubility of these polyphenolic compounds can be increased through the modification of the chemical structure, which may improve oral bioavailability 2. As a result, considerable efforts have been directed towards the development of novel, highly soluble conjugates having clinical profiles that are similar or even superior to those exhibited by the parent molecules in vitro. These include synthetic esters, acyl

The pH-Low Insertion Peptide (pHLIP) offers the potential to deliver drugs selectively to the cytoplasm of cancer cells based on tumor acidosis. The WT pHLIP inserts into membrane with a pH 50 of 6.1 while most solid tumors have extracellular pH (pH e ) of 6.5-7.0. To close this gap, a ** We thank Prof. Dr. Donald M. Engelman (Yale) for discussion and support; Prof. Dr. Eriks Rozners and Prof. Dr. Susan Bane (both of SUNY-Binghamton) for frequent use of their fluorimeter and plate reader, respectively. We also thank Raemer J. Lapid (for assistance in processing data), Rebecca A. Chandler, Meghan M. Bell, Vladyslav Nazarenko, Ilana G. Bandler (for assistance in cell assays) and Emma A. Gordon (for assistance in synthesis). This work was supported by SUNY-Binghamton University (BU) (Start-up funds to M.A. and L.Y., various financial supports to J.O., L.K. and M.C., HHMI-BU undergraduate summer fellowships to C-H. E. and R. L.), NIH (R01-GM073857 for training of M.A. and initial work), and NSF grant CHE-0922815 for the Regional NMR Facility (600 MHz instrument) at SUNY-Binghamton.

Malaria presents an overwhelming public health challenge, particularly in sub-Saharan Africa where vector favourable conditions and poverty prevail, potentiating the disease burden. Behavioural variability of malaria vectors poses a great challenge to existing vector control programmes with insecticide resistance already acquired to nearly all available chemical compounds. Thus, approaches incorporating plant-derived compounds to manipulate semiochemical-mediated behaviours through disruption of mosquito olfactory sensory system have considerably gained interests to interrupt malaria transmission cycle. The combination of push-pull methods and larval control have the potential to reduce malaria vector populations, thus minimising the risk of contracting malaria especially in resource-constrained communities where access to synthetic insecticides is a challenge. In this review, we have compiled information regarding the current status of knowledge on manipulation of larval ecology and chemical-mediated behaviour of adult mosquitoes with plant-derived compounds for controlling mosquito populations. Further, an update on the current advancements in technologies to improve longevity and efficiency of these compounds for field applications has been provided.

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