About
Julio Camarero holds the John A. Biles Professorship in Pharmaceutical Sciences at the University of Southern California's Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences. His research bridges chemistry, biochemistry, and pharmacology — developing novel methods for the chemical synthesis of cyclic peptides and engineering them as drug delivery scaffolds for cancer, HIV, and neurological conditions.
Camarero's group is among the most technically sophisticated in the cyclotide field, combining expertise in native chemical ligation (a powerful chemical synthesis technique), protein engineering, and pharmacological evaluation to produce cyclotide-based drug candidates with precisely defined activities. His research is supported by the NIH, the Department of Defense, the American Cancer Society, and the Melanoma Research Alliance — reflecting both the breadth and the translational significance of his work.
Background & Career
Camarero's scientific training equipped him with deep expertise in the chemistry of protein ligation — the chemical joining of peptide and protein fragments — which he brought to bear on the problem of cyclotide synthesis and engineering. While most natural cyclotides are produced by plant biosynthesis, accessing modified variants for drug development requires precise chemical synthesis that can introduce non-natural amino acids, reporter groups, and therapeutic sequences at specific positions.
Native chemical ligation (NCL), the technique Camarero's group specialises in, allows peptide chains to be joined with complete control over sequence and stereochemistry — making it possible to produce cyclotide variants that would be inaccessible through either biosynthetic or standard solid-phase synthesis approaches. This chemical precision is what enables the group's work on high-potency, target-specific cyclotide drug candidates.
At USC, Camarero built a group that spans the full pipeline from synthesis through pharmacology — designing modified cyclotides, making them using NCL and related methods, and evaluating them against cancer, viral, and neurological targets in cell-based and animal models.
Key Contributions
- NCL-based cyclotide synthesis: Developed and refined native chemical ligation methods for the chemical synthesis of cyclotides with precise modifications — enabling the production of variants carrying therapeutic sequences, non-natural amino acids, and chemical tags at defined positions in the scaffold.
- CXCR4-antagonist cyclotide with anti-HIV activity: Engineered a cyclotide scaffold targeting CXCR4 — a G-protein coupled receptor that HIV-1 uses to enter human immune cells — demonstrating anti-HIV-1 activity in cell culture (PMC3521869). CXCR4 is also a key driver of cancer cell migration and metastasis, making this scaffold relevant to both HIV and oncology.
- p53 and RAS/RAF pathway targeting: Engineered cyclotide-based drug grafting scaffolds targeting cancer-relevant pathways including the p53 tumour suppressor and RAS/RAF oncogenic signalling — two of the most important and historically "undruggable" targets in cancer biology.
- Plug-and-play modular grafting: Developed a "plug and play" modular grafting approach (RSC Chemical Biology, 2024) that bypasses the difficult oxidative folding steps previously required to produce correctly folded cyclotide grafts. This approach produces grafted cyclotides with nanomolar GPCR affinities without the technical bottleneck of disulfide bond formation — a significant practical advance for drug discovery.
- CNS drug delivery: Investigated the ability of cyclotides to penetrate cells and cross the blood-brain barrier — exploring their potential as delivery vehicles for drugs targeting the central nervous system, an area of enormous unmet medical need.
Drug Targets: Cancer, HIV, and the CNS
Camarero's drug development work covers three therapeutic areas where cyclotide scaffolds offer particular promise:
Cancer: The p53 tumour suppressor pathway is disrupted in the majority of human cancers, and RAS/RAF mutations drive some of the most common and treatment-resistant tumour types. Camarero's cyclotide grafts targeting these pathways carry therapeutic sequences in precisely positioned loops of the cyclotide scaffold, held in the correct three-dimensional conformation to interact with their protein targets — an approach that has produced candidates with nanomolar potency.
HIV: The CXCR4 receptor is used by X4-tropic strains of HIV-1 as a co-receptor for cellular entry; blocking it prevents infection. The same receptor promotes cancer cell migration and tumour metastasis. Camarero's CXCR4-targeted cyclotide thus has potential in both HIV treatment and oncology — an example of the multi-indication potential that makes cyclotide drug design attractive.
CNS delivery: Getting drugs across the blood-brain barrier is one of the most challenging problems in pharmaceutical science. Cyclotides' small size, unusual stability, and membrane-active properties make them candidates for CNS drug delivery — a research direction Camarero's group is actively pursuing.
The plug-and-play cyclotide grafting approach published in RSC Chemical Biology (2024) removes one of the major technical barriers to cyclotide drug development — the difficulty of correctly forming the three disulfide bonds of the cystine knot after inserting a therapeutic sequence. Grafted cyclotides produced by this method achieve nanomolar GPCR affinities without the previous oxidative folding bottleneck, significantly accelerating the drug design cycle.
Key Publications
PMC3521869.
Reports the engineering of a cyclotide targeting the CXCR4 receptor and demonstrates its anti-HIV-1 activity in cell culture — one of the first demonstrations of a cyclotide graft with antiviral activity against a clinically relevant target.
RSC Chemical Biology, 2024.
Describes the modular grafting approach that bypasses oxidative folding — producing GPCR-targeted cyclotide grafts with nanomolar affinities without the previous technical bottleneck. A significant methodological advance for the field.
Multiple papers from the Camarero group at USC.
A series of papers developing and applying native chemical ligation to cyclotide synthesis — establishing the chemical toolkit for producing precisely modified cyclotide variants for drug design and mechanistic studies.
Various journals.
Review articles synthesising the drug development potential of cyclotide scaffolds across oncology and antiviral applications — situating Camarero's primary research contributions within the broader landscape of cyclotide drug discovery.